Ligands that modulate RAR receptors

ABSTRACT

Novel ligand compounds having the general formula (I): 
                         
and pharmaceutical/cosmetic compositions comprised thereof are useful in human and veterinary medicine or, alternatively, in cosmetics.

CROSS-REFERENCE TO EARLIER APPLICATIONS

This application is a division of copending U.S. application. Ser. No.11/819,068 filed Jun. 25, 2007, now allowed, which is a continuation ofPCT/EP2005/014217 filed Dec. 21, 2005 and designating the United States,published in the English language as WO 2006/066978 A1 on Jun. 29, 2006,which claims priority under 35 U.S.C. §119 of FR 0413848, filed Dec. 23,2004, and benefit of Provisional Application No. 60/647,383, filed Jan.28, 2005, each hereby expressly incorporated by reference in itsentirety and each assigned to the assignee hereof.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

The present invention relates to novel ligand compounds as usefulindustrial products, which are ligands that modulate RAR receptors. Thisinvention also relates to compositions comprised thereof, to processesfor the preparation of same and to their formulation into pharmaceuticalcompositions useful in human or veterinary medicine, or alternatively,into cosmetic compositions, and to the non-therapeutic applications ofthese compositions.

2. Description of Background and/or Related and/or Prior Art

Compounds with activity of retinoid type (vitamin A and its derivatives)are widely described in the literature as having activity in cellproliferation and differentiation processes. These properties give thisclass of compounds great potential in the treatment or prevention ofnumerous pathologies, and more particularly in dermatology and cancer.Many biological effects of retinoids are mediated by modulating thenuclear retinoic acid receptors (RAR).

The RAR receptors activate transcription by binding to DNA sequenceelements, known as RAR response elements (RARE), in the form of aheterodimer with the retinoid X receptors (known as RXRs).

Three subtypes of human RARs have been identified and described: RARα,RARβ and RARγ.

The prior art described a large number of chemical compounds that areRAR type receptor ligands. In the prior art, examples include U.S. Pat.No. 6,150,413, which describes triaromatic compounds, U.S. Pat. No.6,214,878, which describes stilbene compounds, and U.S. Pat. No.6,218,128, which describes a family of bicyclic or tricyclic molecules.

SUMMARY OF THE INVENTION

Novel compounds that modulate retinoic acid receptors have now beendeveloped.

Thus, the present invention features compounds having the generalformula (I) below:

in which:

R₁ is a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a —CF₃radical;

R₂ is a hydrogen atom, an alkyl or alkoxy radical of 1 to 4 carbon atomsor a chlorine atom;

R₃ is a hydrogen atom, a linear or branched alkyl or alkoxy radical of 1to 10 carbon atoms and preferably 1 to 6 carbon atoms optionallysubstituted with a methoxy group, or alternatively a linear or branchedalkyl radical of 1 to 10 carbon atoms and preferably 1 to 6 carbon atomscontaining an ether function;

R₄ is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms;

R₅ is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms;

or alternatively R₄ and R₅ form, together with the bond —N—C(═Y)—, apyrrolidine, pyrrolidinone, piperidine or piperidinone ring;

Y is two hydrogen atoms or a hetero atom, for example oxygen or sulfur;

Ar is a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl ring;

X is an oxygen atom optionally substituted with an alkyl or alkylamineradical or a C—C single bond;

A is a hydrogen atom or the following formula:

in which:Q is an oxygen atom or an —NH— bond;

R₆ is a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms, acycloalkyl radical of 3 to 6 carbon atoms or a —C(O)CH₃ or —C(O)CH₂CH₃radical;

R₇ and R₇′ represent, independently of each other, a hydrogen atom or ahydroxyl group, with the proviso that R₇ and R₇′ are not simultaneouslya hydroxyl group;

n is 0, 1, 2, 3, 4 or 5;

and the salts of the compounds of formula (I) when R₃ is a hydrogenatom, and also the geometrical isomers of the said compounds of formula(I).

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-3 show a variety of reaction schemes for the ultimatepreparation of the ligand compounds according to the invention.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

When the compounds according to the invention are in the form of a salt,it is preferably an alkali metal or alkaline-earth metal salt, oralternatively a zinc salt or a salt of an organic amine or of an acidicpartner when the compound is itself basic.

According to the present invention, the alkyl radicals of 1 to 3 carbonatoms are preferably selected from among methyl, ethyl, i-propyl andn-propyl radicals.

According to the present invention, the alkyl radicals of 1 to 4 carbonatoms are preferably selected from among methyl, ethyl, i-propyl,i-butyl and t-butyl radicals.

According to the present invention, the alkyl radicals of 1 to 6 carbonatoms are preferably selected from among methyl, ethyl, propyl,i-propyl, butyl, i-butyl, t-butyl, pentyl and hexyl.

According to the present invention, the alkyl radicals of 1 to 10 carbonatoms are linear or branched chains preferably selected from amongmethyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,heptyl, octyl, nonyl and dodecyl.

The term “alkoxy radical having from 1 to 10 carbon atoms” means analkyl radical having from 1 to 10 carbon atoms linked to the rest of themolecule via an oxygen atom. Preferably, the alkoxy radical is selectedfrom among methoxy, ethoxy, isopropyloxy, tert-butoxy and hexyloxyradicals.

Similarly, the term “alkoxy radical having from 1 to 6 carbon atoms”means an alkyl radical having from 1 to 6 carbon atoms linked to therest of the molecule via an oxygen atom. Preferably, the alkoxy radicalis selected from among methoxy, ethoxy, isopropyloxy, tert-butoxy andhexyloxy radicals.

Finally, the term “alkoxy radical having from 1 to 4 carbon atoms” meansan alkyl radical having from 1 to 4 carbon atoms linked to the rest ofthe molecule via an oxygen atom. Preferably, the alkoxy radical isselected from among methoxy, ethoxy, isopropyloxy and tert-butoxyradicals.

According to the present invention, the cycloalkyl radicals of 3 to 6carbon atoms are preferably selected from among cyclopropyl, cyclopentyland cyclohexyl.

According to the present invention, the compounds of formula (I) thatare more particularly preferred are those for which at least one, andpreferably all, of the conditions below are satisfied:

R₁ is a hydrogen atom or a t-butyl or i-propyl radical;

R₂ is a hydrogen atom or a t-butyl or i-propyl radical;

R₃ is a hydrogen atom or an ethyl radical;

R₄ and R₅ are, independently of each other, a methyl or ethyl radical ortogether form a pyrrolidine ring;

A is as defined above in which R₆ is a hydrogen atom, an i-propyl ort-butyl radical, a cycloalkyl radical of 3 to 6 carbon atoms or a—C(O)CH₃ or —C(O)CH₂CH₃ radical.

Among the compounds of formula (I) according to the present invention,especially representative are the following compounds:

-   1. ethyl    3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylate,-   2. ethyl    3″-tert-butyl-4″-diethylamino-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate,-   3.    3″-tert-butyl-4″-diethylamino-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   4. ethyl    4″-(acetylethylamino)-3″-tert-butyl-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate,-   5.    4″-(acetylethylamino)-3″-tert-butyl-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   6.    3″-tert-butyl-4″-diethylamino-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   7. ethyl    3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate,-   8.    3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   9. ethyl    4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate,-   10.    4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   11. ethyl    4″-diethylamino-3″-ethyl-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate,-   12.    4″-diethylamino-3″-ethyl-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   13.    4″-diethylamino-3″-ethyl-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   14. ethyl    4″-diethylamino-3″-ethyl-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate,-   15.    3″-tert-butyl-4″-diethylamino-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate,-   16. ethyl    4″-diethylamino-4′-(3-hydroxypropoxy)-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylate,-   17.    4″-diethylamino-4′-(3-hydroxypropoxy)-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   18. ethyl    3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate,-   19.    3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   20. ethyl    4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylate,-   21.    4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   22. ethyl    3″-tert-butyl-4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate,-   23.    3″-tert-butyl-4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   24. ethyl    3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate,-   25.    3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   26.    4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   27.    3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   28. ethyl    4″-diethylamino-4′-hydroxy-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylate,-   29.    4″-diethylamino-4′-hydroxy-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   30.    3″-tert-butyl-4″-diethylamino-4′-(4-isopropylaminobutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   31.    3″-tert-butyl-4′-(4-isopropylaminobutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   32. ethyl    3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate,-   33.    3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   34. ethyl    3″-tert-butyl-4″-diethylamino-4′-(2,3-dihydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate,-   35.    3″-tert-butyl-4″-diethylamino-4′-(2,3-dihydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   36. ethyl    4″-(acetylethylamino)-3″-tert-butyl-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate,-   37.    4″-(acetylethylamino)-3″-tert-butyl-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   38. ethyl    3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate,-   39.    3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   40. ethyl    3″-tert-butyl-4′-(3-cyclopentylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate,-   41.    3″-tert-butyl-4′-(3-cyclopentylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   42. ethyl    3″-tert-butyl-4′-(3-cyclohexylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate,-   43.    3″-tert-butyl-4′-(3-cyclohexylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   44. ethyl    3″-tert-butyl-4′-(3-tert-butylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate,-   45.    3″-tert-butyl-4′-(3-tert-butylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   46. ethyl    4″-(acetylethylamino)-3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate,-   47.    4″-(acetylethylamino)-3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   48. ethyl    3″-tert-butyl-4″-diethylamino-4′-(3-isopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate,-   49.    3″-tert-butyl-4″-diethylamino-4′-(3-isopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   50. ethyl    4′-(3-aminopropyl)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate,-   51.    4′-(3-aminopropyl)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   52.    [3″-tert-butyl-4-carboxy-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4″-yl]diethylamine    hydrochloride,-   53.    3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-(2-oxopyrrolidin-1-yl)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   54.    3″-tert-butyl-4″-ethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   55.    4′-(3-acetoxypropoxy)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   56.    3″-tert-butyl-4″-diethylamino-4′-(3-propionyloxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   57. methyl    3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate,-   58. isopropyl    3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate,-   59. isobutyl    3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate,-   60.    3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropoxy)-5″-methyl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   61.    4″-diethylamino-4′-(3-hydroxypropoxy)-3″-isopropyl-5″-methyl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   62.    3″-tert-butyl-5″-chloro-4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   63.    4″-diethylamino-4′-(3-hydroxypropoxy)-3″,5″-diisopropyl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   64.    3″,5″-di-tert-butyl-4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   65.    4″-diethylamino-4′-(3-hydroxypropoxy)-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   66.    3″-tert-butyl-4″-(ethylmethylamino)-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   67.    3″-tert-butyl-4″-dimethylamino-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   68.    3″-tert-butyl-4″-(ethylisopropylamino)-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   69.    3″-tert-butyl-4″-(ethylpropylamino)-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   70.    3″-tert-butyl-4″-dipropylamino-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   71.    3″-tert-butyl-4″-(ethylpropionylamino)-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   72.    6-[3′-tert-butyl-4′-diethylamino-6-(2-hydroxyethoxy)biphenyl-3-yl]nicotinic    acid,-   73.    5-[3′-tert-butyl-4′-diethylamino-6-(2-hydroxyethoxy)biphenyl-3-yl]pyridine-2-carboxylic    acid,-   74.    5-[3′-tert-butyl-4′-diethylamino-6-(2-hydroxyethoxy)biphenyl-3-yl]thiophene-2-carboxylic    acid,-   75.    3″-tert-butyl-4′-(2-hydroxyethoxy)-5″-methyl-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   76.    3″-tert-butyl-5″-chloro-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   77.    4′-(2-hydroxyethoxy)-3″-isopropyl-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   78.    3″-ethyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   79.    4′-(2-hydroxyethoxy)-3″,5″-diisopropyl-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   80.    3″,5″-diethyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   81.    3″,5″-dimethyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   82.    4′-(2-acetoxyethoxy)-3″-tert-butyl-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   83.    4′-(2-propionyloxyethoxy)-3″-tert-butyl-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   84. methyl    3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate,-   85. isopropyl    3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate,-   86. isobutyl    3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate,-   87. ethyl    3″-tert-butyl-4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate,-   88. ethyl    3″-tert-butyl-5″-chloro-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate,-   89.    6-[3′-tert-butyl-6-(2-hydroxyethoxy)-4′-pyrrolidin-1-ylbiphenyl-3-yl]nicotinic    acid,-   90.    5-[3′-tert-butyl-6-(2-hydroxyethoxy)-4′-pyrrolidin-1-ylbiphenyl-3-yl]pyridine-2-carboxylic    acid,-   91. ethyl    6-[3′-tert-butyl-6-(2-hydroxyethoxy)-4′-pyrrolidin-1-ylbiphenyl-3-yl]nicotinate,-   92. ethyl    3″-tert-butyl-4′-(3-hydroxypropyl)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate,-   93.    3″-tert-butyl-4′-(3-hydroxypropyl)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   94.    3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-(2-oxopyrrolidin-1-yl)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   95.    3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-(2-oxopiperid-1-yl)-[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   96.    3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-piperid-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic    acid,-   97.    5-[3′-tert-butyl-6-(2-hydroxyethoxy)-4′-pyrrolidin-1-ylbiphenyl-3-yl]thiophene-2-carboxylic    acid.

The present invention also features processes for preparing thecompounds of formula (I), in particular according to the reactionschemes shown in FIGS. 1, 2 and 3.

Synthesis of Advanced Fragments (FIG. 1):

The intermediates of general formula 1 or 2 are prepared from thecommercial starting material 1. Compound 1 is subjected to a first stepof esterification of the carboxylic acid function (a), performed understandard esterification conditions including, for example, the methodsdescribed in “Protective Groups in Organic Synthesis” by T. W. Greene &P. G. M. Wuts, 3rd edition (J. Wiley & Sons), pages 373-377 or in“Comprehensive Organic Transformations” by R. C. Larock, 2^(nd) edition(J. Wiley & Sons), pages 1932-1941. The introduction of a halide(bromide or iodide) into an ortho position of the phenol function (b)may be performed under standard bromination conditions (for example byadding dibromine or an equivalent reagent such as a tetraalkylammoniumtribromide) or standard iodination conditions (for example sodium iodideand sodium hypochlorite), many examples of which may be found in theliterature: see, for example “Comprehensive Organic Transformations” byR. C. Larock, 2^(nd) edition (J. Wiley & Sons), pages 619-628.

The compounds of general formula 3 are then obtained via standardmethods of etherification of phenols (c), for instance an etherificationsimilar to a Williamson reaction starting with corresponding alkylhalides in the presence of a base, or alternatively a reaction ofMitsunobu type with the corresponding hydroxyl derivatives (see“Comprehensive Organic Transformations” by R. C. Larock, 2^(nd) edition(J. Wiley & Sons), pages 889-910 or, respectively: a. Dermer, O. C.,Chem. Rev., 1934, 14, 409 or Nakatsugi, T. Synthesis, 1987, 280: b.Mitsunobu, O. Synthesis 1981, 1). The compounds of formula 3 are, in thecase where the protecting group PG does not coincide with the desiredgroup R₆, subjected to a deprotection step (d) suited to the nature ofPG, the description of which will be found in “Protective Groups inOrganic Synthesis” by T. W. Greene & P. G. M. Wuts, 3rd edition (J.Wiley & Sons) to obtain compound 4 (R₆═H) and is then subjected, whereappropriate, to a standard esterification step (e) (see above) with thecarboxylic acid or acyl halide derivative corresponding to the structureof R₄, in order to obtain the compounds of type 5 in which R₆ is otherthan H.

The intermediates of general formula 7 may be obtained from thecompounds 6 after a first step of bromination (f) in the para position(see above) followed by alkylation or amidation of the aniline function(g) in the presence, respectively, of a dialkyl sulfate or of an alkylhalide and a base (see, for example, Dehmlow, E. V., Tet. Lett. 1985,25, 97 or the reference below) or in the presence of an acyl chloride ora corresponding anhydride and a base (for example Et₃N) in accordancewith the methods described, for example, in “Chemistry of the AminoGroup” by S. Patai (Wiley-Interscience, NY 1968) pages 669-682.Alternatively, when R₄ and R₅, taken together, form a ring from amongthe claimed sub-structures, for example a pyrrolidine ring, thecompounds 7 may be obtained after bromination of 6 and then formation ofthe ring (g), for example in the presence of a 1,4-dihalobutane or a1,5-dihalopentane or the carbonyl analogues thereof, and of a base, orvia a method described in “Chemistry of the Amino Group” by S. Patai(Wiley-Interscience, NY 1968) pages 669-682. Alternatively, when R₄ andR₅, taken together, form a ring from among the claimed sub-structures,the compounds of general formula 7 may also be generated afterpara-bromination (f, see above) and then formation (h) and reduction (i)of a pyrrolidinone, piperidinone, succinimide or piperidine-2,6-dionegroup (see, for example, Ohta, S. Heterocycles 1993, 36 (4), 743;Hubbard, J. L.; J. Heterocycl. Chem., 1992, 29 (4), 719; Akula, M. R.;Synth. Commun. 1998, 28 (11), 2063; Collins, C. J. Tetrahedron Lett.1999, 40 (19), 3673).

Finally, the compounds of general formula 8 may be obtained via asequence of two reactions: the first is an alkylation reaction (h) of asecondary aniline (when Y═H, H, see above) or of an acylaniline (whenY═O), in the presence of a dialkyl sulfate or an alkyl halide and of abase (see, for example, Bisarya, S. C. Synth. Commun. 1992, 22 (22),3305 or the above references); an inversion of steps (h) and (g) whenY═O allows the same precursor of the compounds of general formula 8 tobe obtained. The second reaction is the generation of a boronic acid orboronate function from the bromide group (i), for example by generatingan organolithium or organomagnesium reagent trapped with a trialkylborate (see, for example, Cladingboel, D. E. Org. Process Res. Dev.,2000, 4 (3), 153 or Li, W. J. Org. Chem., 2002, 67 (15), 5394) oralternatively by performing a coupling reaction withbis-dialkoxydiborane or dialkoxyborane in the presence of a catalyst oftransition metal type (see, for example, Ishiyama, T. J. Org. Chem.,1995, 60 (23), 7508 or Murata, M., J. Org. Chem., 1997, 62 (19), 6458).

Synthesis of the Compounds in which X═O (FIG. 2):

The synthesis of the final compounds of general formulae II and 12 maybe performed according to two parallel routes for which only the orderof the reactions changes.

A first route requires the synthesis of the intermediate 9, via acoupling reaction of Suzuki type (j) from the intermediate 2 and theboronate/boronic acid partner of formula 8, under standard Suzukicoupling conditions (see A. Suzuki et al., Synth. Commun., 1981, 11, 513or Sharp, M. J. Tet. Lett. 1985, 26, 5997) or alternatively, whereappropriate, optimized conditions (see, for example, Littke, A. F. etal., J. Am. Chem. Soc., 2000, 122 (17), 4020-4028). The compounds 9 areobtained directly when R₃ is other than H, or after a reaction to revealthe carboxylic acid function, for example by using conditions amongthose described in “Comprehensive Organic Transformations” by R. C.Larock, 2^(nd) edition (J. Wiley & Sons), pages 1959-1968.

The intermediate 9 may also be subjected to the conditions (c) describedabove in order to obtain the compounds of general formula 10.

These compounds of general formula 10 may also be generated via the samemethods (j) described above starting with the intermediates of generalformula 3.

When PG is other than the desired group R₆, 10 may be subjected todeprotection conditions (d) mentioned above to obtain the finalcompounds 11 in which R₆═H, and then, where appropriate, subjected tothe conditions (e) to obtain the compounds 12 in which R₆ is other thanH.

Alternatively, these same final compounds 11 and 12 may be obtained bysubjecting, respectively, the intermediates 4 and 5 to the couplingconditions (j) described above.

Finally, when R₃═H, the advanced intermediates 11 and 12 may besubjected to reactions to reveal the carboxylic acid function, forexample using conditions among those described in “Comprehensive OrganicTransformations” by R. C. Larock, 2^(nd) edition (J. Wiley & Sons),pages 1959-1968.

The compounds of general formula 13 may be obtained after a sequence ofconversion of the primary alcohol function of 11 into an amine, forexample via oxidation (k) followed by reductive amination (I) (see, forexample, “Comprehensive Organic Transformations” by R. C. Larock, 2^(nd)edition (J. Wiley & Sons)) or alternatively conversion of the alcoholinto a halide and substitution of the halogen atom with an amine.

Synthesis of the Claimed Compounds in which X is a Single Bond (FIG. 3):

When X is a single bond, the intermediates of general formula 9 arefirst converted into suitable sulfonyl esters under standard conditions,for example into triflates (see, for example, Robl, J. A. TetrahedronLett. 1990, 31 (24), 3421) (m), and this group is then subjected to anallylation reaction (n), for example in the presence of tributylallyltinand of a transition metal catalyst, for exampletetrakis(triphenylphosphine)palladium (for an example, see Martorell,G.; Garcia-Raso, A.; Saa, J. M.; Tetrahedron Lett. 1990, 31 (16), 2357),to obtain the intermediates of type 14.

The final compounds of general formula 15 may then be obtained via anoxidation reaction (o) of the olefin function, for instance an oxidativehydroboration reaction (see, for example, Luo, F. T.; Negishi, E.; J.Org. Chem., 1983, 48, 5144 or “Comprehensive Organic Transformations” byR. C. Larock, 2^(nd) edition (J. Wiley & Sons), pages 992-993 &1005-1007) in the case where R₇, R₇′═H, H or alternatively via a racemicor enantioselective dihydroxylation reaction, as described, for example,in Van Rheenan, V.; Cha, D. Y.; Hartley, W. M.; Org. Synth., 1978, 58,44 or in “Comprehensive Organic Transformations” by R. C. Larock, 2^(nd)edition (J. Wiley & Sons), pages 996-1001.

When Q=NH, the reaction sequence (k, l) described above for theconversion of the compounds 11 into compounds 13 may be applied, inorder to obtain the compounds of general formula 16. Alternatively, whenQ=O and R₆ is other than H, a simple standard alkylation or acylationreaction of the primary alcohol function of the intermediates ofstructure 15 allows the final compounds of general formula 16 to beobtained.

The compounds according to the invention have modulatory properties onretinoic acid receptors (RAR). This activity on the RARα, β and γreceptors is measured in a transactivation test and quantified by meansof the dissociation constant Kdapp (apparent), as described in Example55.

The preferred compounds of the present invention have a dissociationconstant of less than or equal to 5000 nM, advantageously less than orequal to 1000 nM and preferentially less than or equal to 1 nM.

Preferably, the compounds are at least modulators of receptors of RARγtype, selectively relative to the subtypes α and β, i.e., they have aratio from the Kdapp for the RARα or RARβ receptors, and the Kdapp forthe RARγ receptors, of greater than or equal to 5. Preferably, thisratio RARγ/RARβ or RARγ/RARα is greater than or equal to 10,advantageously greater than or equal to 50 and more advantageouslygreater than or equal to 100.

The present invention also features administration of the compounds offormula (I) as described above, as medicaments.

The compounds according to the invention are particularly suitable inthe following fields of treatment:

1) for treating dermatological complaints, conditions or afflictions,associated with a keratinization disorder relating to celldifferentiation and proliferation, especially for treating common acne,comedones, polymorphonuclear leukocytes, acne rosacea, nodulocysticacne, acne conglobata, senile acne, and secondary acnes such as solaracne, medication-related acne or occupational acne;

2) for treating other types of keratinization disorders, conditions orafflictions, especially ichthyosis, ichthyosiform conditions, Darier'sdisease, palmoplantar keratoderma, leukoplakia and leukoplakiformconditions, and cutaneous or mucous (buccal) lichen;

3) for treating other dermatological complaints, conditions orafflictions having an inflammatory immunoallergic component, with orwithout cell proliferation disorder, and especially all forms ofpsoriasis, whether cutaneous, mucous or ungual psoriasis, and evenpsoriatic rheumatism, or cutaneous atopy, such as eczema, or respiratoryatopy, or even gingival hypertrophy;

4) in the treatment of skin disorders caused by exposure to UVradiation, and also for repairing or combating aging of the skin,whether photoinduced or chronological aging, or for reducing actinicpigmentations and keratosis, or any pathology associated withchronological or actinic aging, such as xerosis;

5) for treating all dermal or epidermal proliferations, whether benignor malignant, and whether of viral origin or otherwise, such as commonwarts, flat warts and verruciform epidermodysplasia, oral or floridpapillomatoses, T lymphoma, and proliferations that may be induced byultraviolet radiation, especially in the case of basocellular andspinocellular epithelioma, and also any precancerous skin lesion such askeratoacanthomas;

6) for treating other dermatological disorders such as immunedermatoses, such as lupus erythematosus, immune bullous diseases andcollagen diseases, such as scleroderma;

7) in the treatment of dermatological or general complaints conditionsor afflictions having an immunological component;

8) for treating certain opthalmological disorders, especiallycorneopathies;

9) for preventing or curing the stigmata of epidermal and/or dermalatrophy induced by local or systemic corticosteroids, or any other formof cutaneous atrophy;

10) in the treatment of any cutaneous or general complaint, condition oraffliction of viral origin;

11) for combating sebaceous function disorders, such as thehyperseborrhoea of acne or simple seborrhoea;

12) for preventing or treating cicatrization disorders, or forpreventing or repairing stretch marks, or alternatively for promotingcicatrization;

13) in the treatment of pigmentation disorders, such ashyperpigmentation, melasma, hypopigmentation or vitiligo;

14) in the treatment of lipid metabolism complaints, conditions orafflictions, such as obesity, hyperlipidaemia, or non-insulin-dependentdiabetes;

15) in the treatment of inflammatory complaints, conditions orafflictions, such as arthritis;

16) in the treatment or prevention of cancerous or precancerousconditions;

17) in the prevention or treatment of alopecia of various origins,especially alopecia caused by chemotherapy or radiation;

18) in the treatment of disorders of the immune system, such as asthma,type I sugar diabetes, multiple sclerosis or other selectivedysfunctions of the immune system; and

19) in the treatment of complaints, conditions or afflictions of thecardiovascular system, such as arteriosclerosis or hypertension.

The present invention also features pharmaceutical compositionscomprising, formulated into a physiologically acceptable medium, atleast one compound of formula (I) as defined above.

This invention also features novel medicinal compositions especiallyuseful for treating the abovementioned complaints, conditions orafflictions, comprising, in a pharmaceutically acceptable support thatis compatible with the mode of administration selected for suchcompositions, at least one compound of formula (I), an optical isomerthereof or a salt thereof.

The compositions according to the invention may be administered, whetherregime or regimen, orally, enterally, parenterally, topically orocularly. The pharmaceutical composition is preferably packaged in aform that is suitable for topical application.

Via the oral route, the composition may be in the form of tablets, gelcapsules, dragees, syrups, suspensions, solutions, powders, granules,emulsions, suspensions of microspheres or nanospheres or lipid orpolymer vesicles allowing a controlled release. Via the parenteralroute, the composition may be in the form of solutions or suspensionsfor infusion or for injection.

The compounds according to the invention are generally administered at adaily dose of about 0.01 mg/kg to 100 mg/kg of body weight, in one ormore dosage intakes.

The compounds are administered systemically, at a concentrationgenerally of from 0.001% to 10% by weight and preferably from 0.01% to1% by weight, relative to the weight of the composition.

Via the topical route, the pharmaceutical composition according to theinvention is more particularly useful for treating the skin and mucousmembranes and may be in liquid, pasty or solid form, and moreparticularly in the form of ointments, creams, milks, pomades, powders,impregnated pads, syndets, solutions, gels, sprays, mousses,suspensions, sticks, shampoos or washing bases. It may also be in theform of suspensions of microspheres or nanospheres or of lipid orpolymer vesicles or gelled or polymer patches allowing a controlledrelease.

The compounds are administered topically at a concentration generally offrom 0.001% to 10% by weight and preferably from 0.01% to 1% by weight,relative to the total weight of the composition.

The compounds of formula (I) according to the invention also findapplications in cosmetics, in particular in body and hair hygiene andespecially for treating acne-prone skin, for promoting regrowth of thehair or for limiting hair loss, for combating the greasy appearance ofthe skin or the hair, in protection against the harmful aspects ofsunlight or in the treatment of physiologically dry skin, and forpreventing and/or combating photoinduced or chronological aging.

The present invention thus also features cosmetic compositionscomprising, formulated into a physiologically acceptable support, atleast one of the compounds of formula (I).

This invention also features the non-therapeutic use of a cosmeticcomposition comprising at least one compound of formula (I) forpreventing and/or treating the signs of aging and/or dry skin.

This invention also features the non-therapeutic use of a cosmeticcomposition comprising at least one compound of formula (I) for body orhair hygiene.

The cosmetic compositions according to the invention containing, in aphysiologically acceptable medium, at least one compound of formula (I)or an optical or geometrical isomer thereof or a salt thereof, may beespecially in the form of a cream, a milk, a gel, suspensions ofmicrospheres or nanospheres or lipid or polymer vesicles, impregnatedpads, solutions, sprays, mousses, sticks, soaps, washing bases orshampoos.

The concentration of compound of formula (I) in the cosmeticcompositions is preferably from 0.001% to 3% by weight, relative to thetotal weight of the composition.

The term “physiologically acceptable medium” means a medium that iscompatible with the skin and optionally with its integuments (eyelashes,nails or hair) and/or mucous membranes.

The pharmaceutical and cosmetic compositions as described above may alsocontain inert additives, or even pharmacodynamically active additives asregards the pharmaceutical compositions, or combinations of theseadditives, and especially:

wetting agents;

flavor enhancers;

preservatives such as para-hydroxybenzoic acid esters;

stabilizers;

moisture regulators;

pH regulators;

osmotic pressure modifiers;

emulsifiers;

UV-A and UV-B screening agents;

antioxidants such as α-tocopherol, butylhydroxyanisole,butylhydroxytoluene, superoxide dismutase, ubiquinol or certainmetal-chelating agents;

depigmenting agents such as hydroquinone, azelaic acid, caffeic acid orkojic acid;

emollients;

moisturizers, for instance glycerol, PEG 400, thiamorpholinone and itsderivatives or urea;

anti-seborrhoeic or anti-acne agents, such as S-carboxymethylcysteine,S-benzylcysteamine, salts thereof or derivatives thereof, or benzoylperoxide;

antibiotics, for instance erythromycin and its esters, neomycin,clindamycin and its esters, and tetracyclines;

anti-fungal agents such as ketoconazole orpoly-4,5-methylene-3-isothiazolidones;

agents for promoting regrowth of the hair, for instance Minoxidil(2,4-diamino-6-piperidinopyrimidine 3-oxide) and its derivatives,Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) andPhenyloin (5,4-diphenylimidazolidine-2,4-dione);

non-steroidal anti-inflammatory agents;

carotenoids and especially β-carotene;

anti-psoriatic agents such as anthralin and its derivatives;

eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-triynoic acid, andesters and amides thereof;

retinoids, i.e., natural or synthetic RXR receptor ligands;

corticosteroids or oestrogens;

α-hydroxy acids and α-keto acids or derivatives thereof, such as lacticacid, malic acid, citric acid, glycolic acid, mandelic acid, tartaricacid, glyceric acid or ascorbic acid, and also salts, amides or estersthereof, or β-hydroxy acids or derivatives thereof, such as salicylicacid and its salts, amides or esters;

ion-channel blockers such as potassium-channel blockers;

or alternatively, more particularly for pharmaceutical compositions, incombination with medicaments known to interfere with the immune system(for example cyclosporin, FK 506, glucocorticoids, monoclonalantibodies, cytokines or growth factors, etc.).

Needless to say, one skilled in this art will take care to select theoptional compound(s) to be added to these compositions such that theadvantageous properties intrinsically associated with the presentinvention are not, or are not substantially, adversely affected by theenvisaged addition.

The present invention also features a cosmetic regime or regimen forenhancing the appearance of the skin, wherein in that a compositioncomprising at least one compound of formula (I) as defined above isapplied to the skin.

Activation of the retinoic acid receptors with the compounds of formula(I) according to the invention makes it possible to obtain skin ofenhanced surface appearance.

In order to further illustrate the present invention and the advantagesthereof, the following examples of specific active compounds are given,as are the results of the biological activities of such compounds andspecific formulations thereof, it being understood that same areintended only as illustrative and in nowise limitative. In said examplesto follow, all parts and percentages are given by weight, unlessotherwise indicated.

EXAMPLES Example 1 Synthesis of ethyl3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylate

a) Preparation of 4-bromo-2-tert-butylaniline

25 g of 2 tert-butylaniline (168 mmol) are dissolved in 250 mL of THF;the reaction mixture is stirred and cooled to 0° C., and 81 g oftetrabutylammonium bromide (TBA.Br₃) (168 mmol) are then addedportionwise while maintaining the temperature from 0° C. and 5° C. Thetemperature is then allowed to rise to about room temperature and themixture is stirred for 10 minutes.

The reaction is stopped by adding 250 mL of water and is then extractedwith 250 mL of ethyl acetate. The organic phases are washed with 1 L ofsaturated Na₂S₂O₅ solution and then dried over magnesium sulfate. Thesolvents are evaporated off and the residue is filtered through a pad ofsilica (pure heptane, then a 3/7 heptane/ethyl acetate mixture).

43.6 g of 4-bromo-2-tert-butylaniline (yield=100%) are obtained in theform of a white solid.

b) Preparation of (4-bromo-2-tert-butylphenyl)diethylamine

6.9 g (0.17 mol) of sodium hydride are suspended in 200 mL oftetrahydrofuran. 13 g (57 mmol) of 4-bromo-2-tert-butylaniline areadded, along with 200 mL of dimethyl sulfoxide, added slowly. Themixture turns blue and, after 30 minutes, 13 mL (0.17 mol) of ethyliodide are added and the reaction medium, which has turned white, isstirred at room temperature for 13 hours. The reaction medium is thenpoured into saturated ammonium chloride solution and extracted withethyl acetate, and the organic phase is then washed twice with water. Itis dried and then concentrated to dryness. The residue is purified bychromatography on silica gel (eluent: 90/10 heptane/ethyl acetate). 14.8g of (4-bromo-2-tert-butylphenyl)diethylamine are obtained (yield=91%)in the form of a yellow oil.

c) Preparation of 3-tert-butyl-4-diethylaminophenylboronic acid

9.8 g (35 mmol) of (4-bromo-2-tert-butylphenyl)diethylamine aredissolved in 118 mL of THF at room temperature, and the reaction mixtureis then cooled to −78° C. 17.5 mL of a 2 M solution of n-BuLi (35 mmol)are added dropwise and the reaction medium is left stirring at −78° C.for 1 hour. 12 mL of triisopropyl borate (B(OiPr)₃) (52 mmol) are addedslowly and the reaction medium is stirred for 15 minutes at −70° C.

The temperature is raised to room temperature and the reaction medium isstirred for 3 hours. The reaction medium is cooled again to −70° C. and69 mL of 1M hydrochloric acid solution (69 mmol) are added. Thetemperature is raised to 0° C. and the reaction medium is stirred for 30minutes. The reaction is extracted after addition of 250 mL of water and250 mL of ethyl acetate. The organic phases are washed with 800 mL ofwater and then dried over sodium sulfate. 6.5 g of3-tert-butyl-4-diethylaminophenylboronic acid are obtained (yield=76%)in the form of a thick oil.

d) Synthesis of ethyl3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylate

To 5.6 g of ethyl 3′-bromo-4′-hydroxy-biphenyl-4-carboxylate (17 mmol)are added 6.5 g of 3-tert-butyl-4-diethylaminophenylboronic acid (26mmol) dissolved in 112 mL of toluene and 30.5 mL of 2M potassiumcarbonate (61 mmol). The reaction medium is stirred and heated to 40°C.; 2 g of tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄) (1.74 mmol)are added and the medium is heated to 110° C. and stirred for 3 hours.The reaction is stopped by adding 200 mL of water and the medium is thenextracted with 200 mL of ethyl acetate. The organic phases are washedwith 400 mL of water and neutralized with 200 mL of saturated NH₄Cl andthen dried over magnesium sulfate. The solvents are evaporated off andthe residue is then purified by chromatography on silica gel (eluent:9/1 heptane/ethyl acetate). 1.2 g of ethyl3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=16%) in the form of an orange solid.

¹H NMR (CDCl₃, 400 MHz): 1.14 (t, J=7.4 Hz, 6H); 1.44 (t, J=7.6H, 3H);1.51 (s, 9H); 2.94 (bs, 2H); 3.00 (bs, 2H); 4.42 (q, J=7.6 Hz, 2H); 5.49(s, 1H); 7.11 (d, J=8.5 Hz, 1H); 7.33-7.41 (m, 2H); 7.53-7.57 (m, 3H);7.68 (d, J=6.7 Hz, 2H); 8.11 (d, J=6.7 Hz, 2H).

Example 2 Synthesis of ethyl3″-tert-butyl-4″-diethylamino-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate

a) Preparation of ethyl3″-tert-butyl-4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate

1 g of ethyl3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylateobtained in Example 1d (2.2 mmol) are dissolved in 20 mL ofdimethylformamide under a nitrogen atmosphere. 880 mg (2.7 mmol) ofcaesium carbonate are added. The reaction medium stirred at roomtemperature turns yellow. 0.64 mL of1-bromo-4-(tert-butyldimethylsilanyloxy)butane (2.4 mmol) is then addedand the reaction medium is heated at 80° C. for 18 hours. The reactionmedium is then cooled to room temperature and then filtered. Thesolvents are evaporated off and the residue obtained is purified bychromatography on silica gel (eluent: 70/30 heptane/ethyl acetate).

1.4 g of ethyl3″-tert-butyl-4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=99%) in the form of an oil.

b) Synthesis of ethyl3″-tert-butyl-4″-diethylamino-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate

1.6 g of ethyl3″-tert-butyl-4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate(2.5 mmol) are dissolved in 20 mL of tetrahydrofuran under a nitrogenatmosphere.

3 mL of a 1M solution of tetrabutylammonium fluoride are then addeddropwise. The reaction medium is stirred at room temperature for 3hours, and the reaction is then stopped by adding 10 mL of water andthen extracted with ethyl acetate. The organic phases are combined anddried over magnesium sulfate. The solvents are evaporated off and theresidue is precipitated from 10 mL of heptane and filtered. 900 mg ofethyl3″-tert-butyl-4″-diethylamino-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=92%).

¹H NMR (CDCl₃-400 MHz): 1.12 (t, J=7.8 Hz, 6H); 1.43 (t, J=7.5 Hz, 3H);1.51 (s, 9H); 1.64-1.71 (m, 2H); 1.85-2.07 (m, 2H); 2.91 (bs, 2H); 2.99(bs, 2H); 3.62 (t, J=6.1 Hz, 2H); 4.08 (t, J=6.1 Hz, 2H); 4.41 (t, J=7.5Hz, 2H); 7.07 (d, J=8.0 Hz, 1H); 7.30 (d, J=8.0 Hz, 1H); 7.38 (d, J=8.0Hz, 1H); 7.56-7.59 (m, 1H); 7.62-7.64 (m, 2H); 7.68 (d, J=8.2 Hz, 2H);8.11 (d, J=8.2 Hz, 2H).

Example 3 Synthesis of3″-tert-butyl-4″-diethylamino-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

a) Synthesis of3″-tert-butyl-4″-diethylamino-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

0.9 mL of aqueous 1N sodium hydroxide solution is added to a solution of300 mg of ethyl3″-tert-butyl-4″-diethylamino-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate(Example 2b) in a mixture of 10 mL of tetrahydrofuran and 3 mL of water.The reaction medium is stirred at room temperature for 12 hours. 0.5 mLof aqueous 1N sodium hydroxide solution is then added. After 12 hours atroom temperature, the reaction medium is heated to 50° C. and then leftat room temperature for 3 days. The reaction is stopped by adding 5 mLof water. The reaction medium is acidified to pH 5 by adding aqueous 1Nhydrochloric acid solution and is then extracted with ethyl acetate. Theorganic phase is dried over magnesium sulfate. The solid obtained istaken up in heptane and then filtered. 235 mg of3″-tert-butyl-4″-diethylamino-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained in the form of a white solid (yield=83%, m.p.=165°C.).

¹H NMR (DMSO-D₆ 400 MHz): 1.06 (t, 6H); 1.45 (s, 9H); 1.52 (m, 2H); 1.73(m, 2H); 2.9 (m, 4H); 3.39 (t, 2H); 4.05 (t, 2H); 7.2 (dd, J=8.5 Hz,1H); 7.3 (dd, J=8.15 Hz, 1H); 7.39 (d, J=6.93 Hz, 1H); 7.6 (s, 1H); 7.64(s, 1H); 7.66 (d, J=8.5 Hz 2H); 7.8 (d, 2H, J=8.3 Hz); 7.97 (d, J=8.3Hz, 1H).

Example 4 Synthesis of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate

a) Preparation of (4-bromo-2-tert-butylphenyl)ethylamine

In a 1 L three-necked flask under a nitrogen atmosphere, equipped with amagnetic stirrer, 28 g (123 mmol) of 4-bromo-2-tert-butylphenylamine aredissolved in 280 mL of dimethylformamide. 5.4 g (135 mmol) of sodiumhydride (60%) are added portionwise and the reaction medium is stirredfor 10 minutes. 140 mL of dimethyl sulfoxide are then added slowly. Thereaction medium is stirred at room temperature for 2 hours, 23 g (147mmol, 11.8 mL) of ethyl iodide are introduced dropwise and the medium isthen stirred for 18 hours at room temperature. The reaction medium ispoured into 1 L of water and extracted three times with ethyl acetate.

The organic phases obtained are combined and washed with water, driedover anhydrous magnesium sulfate, filtered and evaporated to give areddish oil. This residue is purified on silica (eluent: 95/5heptane/ethyl acetate) to give 25 g (yield=79%) of(4-bromo-2-tert-butylphenyl)ethylamine in the form of a dark reddishoil.

b) Preparation of N-(4-bromo-2-tert-butylphenyl)-N-ethylacetamide

In a 250 mL three-necked flask under a nitrogen atmosphere, equippedwith a magnetic stirrer, 15 g (58.5 mmol) of(4-bromo-2-tert-butylphenyl)ethylamine are dissolved in 150 mL ofdichloromethane. 8.9 g (87.8 mmol, 12.2 mL) of triethylamine and 0.72 g(5.9 mmol) of 4-dimethylaminopyridine are added. 11.5 g (146 mmol, 2.5mL) of acetyl chloride are added dropwise and the reaction medium isstirred for 1 hour at room temperature. The reaction medium is pouredinto 250 mL of water and extracted twice with dichloromethane. Theorganic phases obtained are combined and washed with water, dried overanhydrous magnesium sulfate, filtered and evaporated to give a blackishoil. This oil is purified by chromatography on silica (eluent: 80/20heptane/ethyl acetate) to give 15 g (yield=86%) ofN-(4-bromo-2-tert-butylphenyl)-N-ethylacetamide in the form of an orangeoil.

c) Preparation ofN-[2-tert-butyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]-N-ethylacetamide

In a 250 mL three-necked flask under a nitrogen atmosphere, equippedwith a magnetic stirrer, 10 g (33.5 mmol) ofN-(4-bromo-2-tert-butylphenyl)-N-ethylacetamide are dissolved in 100 mLof dimethylformamide. The solution is then degassed by sparging withnitrogen for 15 minutes. 13.2 g (134 mmol) of potassium acetate, 12.8 g(50.3 mmol) of bis(pinacolato)diborane and 2.73 g (3.35 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) are thenadded; the reaction medium is heated at 80° C. and stirred at thistemperature for 3 hours. The reaction medium is poured into 500 mL ofwater and extracted twice with ethyl acetate. The organic phasesobtained are combined and washed with water, dried over anhydrousmagnesium sulfate, filtered and evaporated to give a blackish oil. Thisoil is purified by chromatography on silica (eluent: 90/10 heptane/ethylacetate) to give 12 g (yield=100%) ofN-[2-tert-butyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]-N-ethylacetamidein the form of a beige-colored powder.

d) Preparation of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 1d, by reacting 2 g of ethyl3′-bromo-4′-hydroxy-biphenyl-4-carboxylate (6 mmol) with 2.7 g ofN-[2-tert-butyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]-N-ethylacetamide(9 mmol) in the presence of tetrakis(triphenylphosphine)palladium. 1.9 gof ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylate(yield=70%) are obtained in the form of a beige-colored powder.

e) Preparation of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 2a, by reacting 260 mg of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylate(0.56 mmol) in 12 mL of dimethylformamide with 225 mg of caesiumcarbonate and 0.16 mL of 1-bromo-4-(tert-butyldimethylsilanyloxy)butane,310 mg of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-[1,1′;3′,1″]terphenyl-4-carboxylate(yield=99%) are obtained in the form of an oil.

f) Synthesis of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 2b, by reacting 320 mg of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-[1,1′;3′,1″]terphenyl-4-carboxylatein 10 mL of tetrahydrofuran with 0.5 mL of 1M tetrabutylammoniumfluoride, 270 mg of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=99%).

¹H NMR (CDCl₃-400 MHz): 1.27 (t, 3H); 1.42 (s, 9H); 1.43 (t, 3H);1.63-1.69 (m, 2H); 1.89 (s, 3H); 1.87-1.91 (m, 2H); 2.85-2.91 (m, 2H);3.60-3.64 (m, 2H); 4.11 (t, J=6.1 Hz, 2H); 4.42 (t, J=7.5 Hz, 2H); 7.06(d, J=8.0 Hz, 1H); 7.10 (d, J=8.0 Hz, 1H); 7.42 (d, J=8.0 Hz, 1H);7.61-7.63 (m, 2H); 7.68 (d, J=8.2 Hz, 2H); 7.81 (s, 1H); 8.12 (d, J=8.2Hz, 2H).

Example 5 Synthesis of4″-(acetylethylamino)-3″-tert-butyl-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

a) Synthesis of4″-(acetylethylamino)-3″-tert-butyl-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 270 mg of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylatewith 0.8 mL and then 0.4 mL of aqueous 1N sodium hydroxide solution in amixture of 8 mL of tetrahydrofuran and 2 mL of water. 195 mg of4″-(acetylethylamino)-3″-tert-butyl-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained in the form of a white solid (yield=95%, m.p.=75° C.).

¹H NMR (DMSO, 400 MHz): 1.26 (m, 3H); 1.43 (s, 9H); 1.67 (m, 2H); 1.87(s, 3H); 1.89 (m, 2H); 2.92 (m, 1H); 3.63 (m, 2H); 4.11 (m, 2H); 4.4 (m,1H); 7.0 (m, 1H); 7.36 (m, 1H); 7.58 (m, 4H); 7.77 (m, 1H); 8.12 (m,2H).

Example 6 Synthesis of3″-tert-butyl-4″-diethylamino-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

a) Preparation of ethyl4′-(2-acetoxyethoxy)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate

850 mg (1.9 mmol) of ethyl3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylate(obtained in Example 1d) are dissolved in dimethylformamide undernitrogen. 92 mg (2.3 mmol) of 60% sodium hydride are added. After 20minutes at room temperature, 0.25 mL (2.3 mmol) of 2-bromoethan-1-olacetate are added and the mixture is stirred for 24 hours at roomtemperature and then poured into saturated ammonium chloride solutionand extracted with ethyl acetate. The organic phase is washed with waterand then dried and evaporated. The residue obtained is purified bychromatography on silica gel (eluent: 70/30 heptane/ethyl acetate). 1 gof ethyl4′-(2-acetoxyethoxy)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylateis obtained (yield=99%) in the form of a colorless oil.

b) Synthesis of3″-tert-butyl-4″-diethylamino-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

1 g (1.9 mmol) of ethyl4′-(2-acetoxyethoxy)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylateis placed in 50 mL of tetrahydrofuran and 19 mL (19 mmol) of 1N sodiumhydroxide solution are added. The mixture is stirred at reflux for 12hours. The yellow solution obtained is poured into saturated ammoniumchloride solution, the pH is adjusted to 5-6 with 1N hydrochloric acidsolution and the mixture is then extracted with ethyl acetate. Theorganic phase is dried over magnesium sulfate and then concentrated todryness. 455 mg of3″-tert-butyl-4″-diethylamino-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained in the form of a white solid (yield=52%, m.p.=216° C.)

¹H NMR (DMSO, 400 MHz): 1.06 (t, J=7.2 Hz, 6H); 1.47 (s, 9H); 2.84 (m,2H); 2.94 (m, 2H); 4.11 (m, 2H); 7.23 (d, J=8 Hz, 1H); 7.32 (d, J=8 Hz,1H); 7.48 (dd, J=1.6 Hz, 8.4 Hz, 1H); 7.66 (dd, J=1.2 Hz, 4 Hz, 2H);7.69 (d, J=2 Hz, 1H); 7.99 (d, J=8 Hz, 2H); 7.82 (d, J=8 Hz, 2H).

Example 7 Synthesis of ethyl3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate

a) Preparation of ethyl3″-tert-butyl-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 2a, by reacting 1 g of ethyl3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylate(obtained in Example 1d) (2.2 mmol) in 20 mL of dimethylformamide with880 mg (2.7 mmol) of caesium carbonate and 0.6 mL of1-bromo-3-(tert-butyldimethylsilanyloxy)propane (2.4 mmol). 1.35 g ofethyl3″-tert-butyl-4′-[4-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=99%) in the form of an oil.

b) Synthesis of ethyl3″-tert-butyl-4″-diethylamino-4′-(4-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 2b, by reacting 1 g of ethyl3″-tert-butyl-4′-[4-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate(1.62 mmol) in 25 mL of tetrahydrofuran with 2 mL of 1Mtetrabutylammonium fluoride. 790 mg of ethyl3″-tert-butyl-4″-diethylamino-4′-(4-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=97%, m.p.=114-115° C.).

¹H NMR (DMSO, 400 MHz): 1.10 (t, J=7.1 Hz, 6H); 1.41 (t, J=7.1 Hz, 3H);1.49 (s, 9H); 1.81 (m, 1H); 2.90 (bs, 2H); 3.0 (bm, 2H); 3.88 (m, 2H);4.13 (t, J=4.4 Hz, 2H); 4.40 (q, J=7.1 Hz, 2H); 7.08 (d, J=8.5 Hz, 1H);7.30 (m, 1H); 7.36 (m, 1H); 7.56 (m, 1H); 7.62 (m, 2H); 7.66 (d, J=8.4Hz, 2H); 8.09 (d, J=8.1 Hz, 2H).

Example 8 Synthesis of3″-tert-butyl-4″-diethylamino-4′-(2-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 870 mg of ethyl3″-tert-butyl-4″-diethylamino-4′-(4-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate(Example 6b, 1.7 mmol) with 15 mL of 1N sodium hydroxide solution. 410mg of3″-tert-butyl-4″-diethylamino-4′-(2-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained in the form of a white solid (yield=51%, m.p.=193°C.).

¹H NMR (DMSO, 400 MHz): 1.05 (t, J=7 Hz, 6H); 1.46 (s, 9H); 1.85 (t, J=6Hz, 2H); 2.50 (m, 2H); 2.95 (m, 2H); 3.51 (t, J=8 Hz, 2H); 4.12 (t, J=4Hz, 2H); 4.50 (s, 1H); 7.22 (d, J=8 Hz, 1H); 7.32 (d, J=8 Hz, 1H); 7.41(dd, J=1.6 Hz, 8 Hz, 1H); 7.61 (d, J=1.6 Hz, 1H); 7.65 (d, J=2.4 Hz,1H); 7.70 (dd, J=2 Hz, 8 Hz, 1H); 7.83 (d, J=8.4 Hz, 2H); 7.99 (d, J=8Hz, 2H); 13.1 (s, 1H).

Example 9 Synthesis of ethyl4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate

a) Preparation of 4-Diethylaminophenylboronic acid

In a manner similar to that of Example 1c, by reacting 5 g of(4-bromo-phenyl)diethylamine (21.9 mmol) with 13 mL of 2.0 Mn-butyllithium solution and 6 mL (26 mmol) of triisopropyl borate. 4 gof 4-diethylaminophenylboronic acid (yield=94%) are obtained in the formof a white solid.

b) Preparation of ethyl3′-bromo-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]biphenyl-4-carboxylate

In a manner similar to that of Example 2a, by reacting 3 g of ethyl3′-bromo-4′-hydroxy-biphenyl-4-carboxylate (9.3 mmol) in 100 mL ofdimethylformamide with 448 mg (11 mmol) of sodium hydride and 2.6 mL of1-bromo-3-(tert-butyldimethylsilanyloxy)propane (11 mmol). 2.95 g ofethyl3′-bromo-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]biphenyl-4-carboxylateare obtained (yield=64%) in the form of an oil.

c) Preparation of ethyl4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 1d, by reacting 1 g of ethyl3′-bromo-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]biphenyl-4-carboxylate(2 mmol) with 580 mg of 4-diethylaminophenylboronic acid (3 mmol) in thepresence of tetrakis(triphenylphosphine)palladium. 1.15 g of ethyl4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate(yield=100%) are obtained in the form of a colorless oil.

d) Synthesis of ethyl4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 2b, by reacting 730 mg of ethyl4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate(1.3 mmol) in 25 mL of tetrahydrofuran with 1.6 mL of 1Mtetrabutylammonium fluoride. 430 mg of ethyl4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=74%).

¹H NMR (CDCl₃, 400 MHz): 1.22 (t, J=7.4 Hz, 6H); 1.43 (t, J=7.6H, 3H);2.05 (m, 2H); 3.42 (q, J=7.4 Hz, 4H); 3.81 (m, 2H); 4.17 (t, J=5.7 Hz,2H); 4.41 (q, J=7.6 Hz, 2H); 6.76 (d, J=8.9 Hz, 1H); 7.08 (d, J=8.1 Hz,2H); 7.45-7.47 (m, 2H); 7.52 (dd, J₁=2.3 Hz, J₂=8.6 Hz, 1H); 7.62 (d,J=2.4 Hz, 1H); 7.67 (d, J=6.7 Hz, 2H); 8.10 (d, J=6.7 Hz, 2H).

Example 10 Synthesis of4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 430 mg of ethyl4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate(Example 8d, 0.9 mmol) with 10 mL of 1N sodium hydroxide solution, 100mg of4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained in the form of a yellow solid (yield=25%, m.p.=200°C.).

HPLC Thermo Aquasil C₁₈, 3 microns, 2×150 mm, mobile phase: A (CH₃CN/0.1v/v HCO₂H); B (H₂O/0.1 v/v HCO₂H), Flow rate: 0.5 mL/minutes. Gradient:0 min: 90% B, 0-20 min: 90-5% B, 20-30 min: 5% B; retention time: 10.01min, purity: 96%, MS (ESI) m/z 420.22 (M+H)⁺

Example 11 Synthesis of ethyl4″-diethylamino-3″-ethyl-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate

a) Preparation of (4-bromo-2-ethylphenyl)diethylamine

In a manner similar to that of Example 1b, by reacting 6 g (0.15 mol) ofsodium hydride with 10 g (50 mmol) of 4-bromo-2-ethylaniline, 11.3 g of(4-bromo-2-ethylphenyl)diethylamine are obtained (yield=88%) in the formof a yellow oil.

b) Preparation of 4-diethylamino-3-ethylphenylboronic acid

In a manner similar to that of Example 1c, by reacting 3 g of(4-bromo-2-ethylphenyl)diethylamine (11.7 mmol) with 5.2 mL of a 2.5 Msolution of n-butyllithium and 3.2 mL (14 mmol) of triisopropyl borate,0.9 g of 4-diethylamino-3-ethylphenylboronic acid (yield=35%) isobtained in the form of a white solid.

c) Preparation of ethyl4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino-3″-ethyl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 1d, by reacting 1.4 g (2.9 mmol)of ethyl3′-bromo-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]biphenyl-4-carboxylate(obtained in Example 5b) with 900 mg of4-diethylamino-3-ethylphenylboronic acid (4 mmol) in the presence oftetrakis(triphenylphosphine)palladium, 674 mg of ethyl4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino-3″-ethyl[1,1′;3′,1″]terphenyl-4-carboxylate(yield=39%) are obtained in the form of a colorless oil.

d) Synthesis of ethyl4″-diethylamino-3″-ethyl-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 2b, by reacting 660 mg of ethyl4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino-3″-ethyl[1,1′;3′,1″]terphenyl-4-carboxylate(1.1 mmol) in 25 mL of tetrahydrofuran with 1.2 mL of 1Mtetrabutylammonium fluoride. 280 mg of ethyl4″-diethylamino-3″-ethyl-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=52%).

¹H NMR (CDCl₃, 400 MHz): 1.05 (t, J=7.4 Hz, 6H); 1.28 (t, J=7.5 Hz, 3H);1.44 (t, J=7.6H, 3H); 2.02 (m, 2H); 2.80 (q, J=7.5 Hz, 2H); 3.02 (q,J=7.4 Hz, 4H); 3.77 (q, J=5.6 Hz, 2H); 4.17 (t, J=5.7 Hz, 2H); 4.42 (q,J=7.6 Hz, 2H); 7.10 (d, J=8.5 Hz, 1H); 7.18 (d, J=8.1 Hz, 1H); 7.35 (dd,J₁=2.1 Hz, J₂=8.2 Hz, 1H); 7.44 (d, J=2.1 Hz, 1H); 7.57 (dd, J₁=2.4 Hz,J₂=8.5 Hz, 1H); 7.63 (d, J=2.4 Hz, 1H); 7.57 (dd, J₁=2.4 Hz, J₂=8.5 Hz,1H); 7.64 (d, J=2.4 Hz, 1H); 7.69 (d, J=6.7 Hz, 2H); 8.11 (d, J=6.7 Hz,2H).

Example 12 Synthesis of4″-diethylamino-3″-ethyl-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

a) Synthesis of4″-Diethylamino-3″-ethyl-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

Into a 25 mL three-necked flask under a nitrogen atmosphere, equippedwith a magnetic stirrer, are placed 270 mg (0.57 mmol) of ethyl4″-diethylamino-3″-ethyl-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate(Example 10d) and 22 mg (5.7 mmol) of solid sodium hydroxide in 5.4 mLof tetrahydrofuran. The reaction medium is heated at the refluxtemperature of the tetrahydrofuran for 5 hours. The reaction medium isconcentrated under vacuum. The crude reaction product obtained is takenup in water and the pH of the medium thus obtained is adjusted to pH=4by addition of hydrochloric acid solution in a proportion of 1 mol/L.The precipitate obtained, after stirring for 30 minutes, is purified bychromatography on silica (eluent: 40/60 heptane/ethyl acetate) to give,after evaporation of the fractions, 80 mg (yield=31%) of4″-diethylamino-3″-ethyl-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid in the form of a cream-colored powder (m.p.=204° C.).

¹H NMR (DMSO, 400 MHz): 1.02 (t, J=7.2 Hz, 6H); 1.25 (t, J=7.2 Hz, 3H);2.02 (m, 2H); 2.78 (q, J=7.6 Hz, 2H); 3.01 (q, J=6.8 Hz, 4H); 3.76 (t,J=5.6 Hz, 2H); 4.18 (t, J=5.6 Hz, 2H); 7.08 (d, J=8.4 Hz, 1H); 7.16 (d,J=8.0 Hz, 1H); 7.33 (dd, J₁=2.0 Hz, J₂=8.4 Hz, 1H); 7.42 (d, J=1.6 Hz,1H); 7.56 (dd, J₁=2.0 Hz, J₂=8.4 Hz, 1H); 7.63 (d, J=2.4 Hz, 1H); 7.70(d, J=8.4 Hz, 2H); 8.14 (d, J=8.4 Hz, 2H).

Example 13 Synthesis of4″-diethylamino-3″-ethyl-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

a) Preparation of ethyl4′-(2-acetoxyethoxy)-3′-bromobiphenyl-4-carboxylate

In a manner similar to that of Example 6a, by reacting 2 g (6 mmol) ofethyl 3′-bromo-4′-hydroxybiphenyl-4-carboxylate with 320 mg (8 mmol) of60% sodium hydride and 0.7 mL (7 mmol) 2-bromoethan-1-ol acetate, 2.2 gof ethyl 4′-(2-acetoxyethoxy)-3′-bromobiphenyl-4-carboxylate areobtained (yield=95%) in the form of a colorless oil.

b) Preparation of ethyl2′-(2-acetoxyethoxy)-3-tert-butyl-4-diethylamino[1,1′;4′,1″]terphenyl-3″-carboxylate

In a manner similar to that of Example 1d, by reacting 400 mg of ethyl4′-(2-acetoxyethoxy)-3′-bromobiphenyl-4-carboxylate (1 mmol) with 340 mgof 4-diethylamino-3-ethylphenylboronic acid (1.5 mmol) in the presenceof tetrakis(triphenylphosphine)palladium, 500 mg of ethyl2′-(2-acetoxyethoxy)-3-tert-butyl-4-diethylamino[1,1′;4′,1″]terphenyl-3″-carboxylate(yield=97%) are obtained in the form of a white solid.

c) Synthesis of4″-diethylamino-3″-ethyl-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 6b, by reacting 690 mg (1.4 mmol)of ethyl2′-(2-acetoxyethoxy)-3-tert-butyl-4-diethylamino[1,1′;4′,1″]terphenyl-3″-carboxylatewith 550 mg (14 mmol) of sodium hydroxide, 470 mg of4″-diethylamino-3″-ethyl-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=79%) in the form of a white solid (m.p.=206°C.).

¹H NMR (DMSO, 400 MHz): 1.05 (t, J=7.0 Hz, 6H); 1.27 (t, J=7.6 Hz, 3H);2.80 (q, J=7.2 Hz, 2H); 3.03 (q, J=7.2 Hz, 4H); 3.90 (m, 2H), 4.15 (m,2H); 7.09 (m, 1H); 7.18 (m, 1H); 7.38 (m, 1H); 7.47 (m, 1H); 7.56 (m,1H); 7.7 (m, 3H); 8.18 (d, J=8.4 Hz, 2H).

Example 14 Synthesis of ethyl4″-diethylamino-3″-ethyl-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate

a) Synthesis of ethyl4″-diethylamino-3″-ethyl-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate

6.6 g of ethyl2′-(2-acetoxyethoxy)-3-tert-butyl-4-diethylamino[1,1′;4′,1″]terphenyl-3″-carboxylate(obtained in Example 13b) are dissolved in 200 mL of a 2% solution ofpotassium carbonate in ethanol. The reaction medium is stirred for 2hours at room temperature and then poured into saturated ammoniumchloride solution and extracted with ethyl acetate. The residue obtainedis purified by chromatography on silica gel (eluent: 7/3 heptane/ethylacetate). 4 g of ethyl4″-diethylamino-3″-ethyl-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate(yield=66%) are obtained in the form of a white solid (m.p.=97° C.).

¹H NMR (DMSO, 400 MHz): 1.06 (t, J=7.0 Hz, 6H); 1.28 (t, J=7.5 Hz, 3H);1.44 (t, J=7.1 Hz, 3H); 1.91 (bs, 1H); 2.80 (q, J=7.5 Hz, 2H); 3.04 (q,J=7.0 Hz, 4H); 3.90 (bs, 2H); 4.16 (m, 2H); 4.42 (q, J=7.1 Hz, 2H); 7.10(d, J=8.5 Hz, 1H); 7.18 (d, J=8.5 Hz, 1H); 7.37 (dd, J=2.1 hz, 8.2 Hz,1H); 7.47 (d, J=2.0 Hz, 1H); 7.57 (dd, J=2.4 Hz, 8.5 Hz, 1H); 7.66 (m,1H); 7.69 (d, J=8.4 Hz, 2H); 8.12 (d, J=8.4 Hz, 2H).

Example 15 Synthesis of ethyl3″-tert-butyl-4″-diethylamino-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate

a) Synthesis of Ethyl3″-tert-butyl-4″-diethylamino-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 14a, by reacting 490 mg of ethyl4′-(2-acetoxyethoxy)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate(0.9 mmol) obtained in Example 6a with 10 mL of a 2% solution ofpotassium carbonate in ethanol, 400 mg of ethyl3″-tert-butyl-4″-diethylamino-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=82%) in the form of a white solid (m.p.=127° C.).

¹H NMR (DMSO, 400 MHz): 1.10 (t, J=7.0 Hz, 6H); 1.41 (t, J=7.1 Hz, 3H);1.49 (s, 9H); 1.81 (bs, 1H); 2.90 (bs, 2H); 3.0 (bs, 2H); 3.87 (m, 2H);4.13 (m, 2H); 4.40 (q, J=7.1 Hz, 2H); 7.08 (d, J=8.5 Hz, 1H); 7.30 (d,J=8.5 Hz, 1H); 7.35 (dd, J=2.1 hz, 8.2 Hz, 1H); 7.56 (dd, J=2.0 Hz, 8.1Hz, 1H); 7.62 (dd, J=2.4 Hz, 8.5 Hz, 1H); 7.65 (m, 1H); 7.66 (d, J=8.4Hz, 2H); 8.09 (d, J=8.4 Hz, 2H).

Example 16 Synthesis of ethyl4″-diethylamino-4′-(3-hydroxypropoxy)-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylate

a) Preparation of (4-bromo-2-methylphenyl)diethylamine

In a manner similar to that of Example 1b, by reacting 4.7 g (0.12 mol)of sodium hydride with 10 g (54 mmol) of 4-bromo-2-methylaniline, 8 g of(4-bromo-2-methylphenyl)diethylamine are obtained (yield=62%) in theform of a yellow oil.

b) Preparation of 4-diethylamino-3-methylphenylboronic acid

In a manner similar to that of Example 1c, by reacting 8 g of(4-bromo-2-methylphenyl)diethylamine (33 mmol) with 16 mL of a 2.5 Msolution of n-butyllithium and 11.5 mL (50 mmol) of triisopropyl borate,7.6 g of 4-diethylamino-3-methylphenylboronic acid (yield=100%) areobtained in the form of a thick oil.

c) Preparation of ethyl4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 1d, by reacting 1 g (2 mmol) ofethyl3′-bromo-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]biphenyl-4-carboxylate(obtained in Example 6b) with 630 mg of4-diethylamino-3-methylphenylboronic acid (3 mmol) in the presence oftetrakis(triphenylphosphine)palladium, 1.1 g of ethyl4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylate(yield=95%) are obtained in the form of a pale yellow oil.

d) Synthesis of ethyl4″-diethylamino-4′-(3-hydroxypropoxy)-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 2b, by reacting 1.1 g of ethyl4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylate(1.9 mmol) in 25 mL of tetrahydrofuran with 2.3 mL of 1Mtetrabutylammonium fluoride, 130 mg of ethyl4″-diethylamino-4′-(3-hydroxypropoxy)-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=15%).

¹H NMR (CDCl₃, 400 MHz): 1.06 (t, J=7.4 Hz, 6H); 1.44 (t, J=7.6H, 3H);2.05 (m, 2H); 2.37 (s, 3H); 3.05 (q, J=7.4 Hz, 4H); 3.78 (q, J=5.6 Hz,2H); 4.19 (t, J=5.7 Hz, 2H); 4.42 (q, J=7.6 Hz, 2H); 7.09 (d, J=8.5 Hz,1H); 7.13 (d, J=8.1 Hz, 1H); 7.35-7.39 (m, 2H); 7.57 (dd, J₁=2.4 Hz,J₂=8.5 Hz, 1H); 7.63 (d, J=2.4 Hz, 1H); 7.68 (d, J=6.7 Hz, 2H); 8.11 (d,J=6.7 Hz, 2H).

Example 17 Synthesis of4″-diethylamino-4′-(3-hydroxypropoxy)-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 12a, by reacting 130 mg (0.3mmol) of ethyl4″-diethylamino-4′-(3-hydroxypropoxy)-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylate(Example 15d) with 3 mL of 1N sodium hydroxide solution. 60 mg of4″-diethylamino-4′-(3-hydroxypropoxy)-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained in the form of a white solid (yield=46%, m.p.=208°C.).

HPLC Thermo Aquasil C₁₈, 3 microns, 2×150 mm, mobile phase: A (CH₃CN/0.1v/v HCO₂H); B (H₂O/0.1 v/v HCO₂H), Flow rate: 0.5 mL/minutes. Gradient:0 min: 90% B, 0-20 min: 90-5% B, 20-30 min: 5% B; retention time: 8.95min, purity: 92%, MS (ESI) m/z 434.3 (M+H)⁺.

Example 18 Synthesis of ethyl3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate

a) Preparation of 1-(4-bromo-2-tert-butylphenyl)pyrrolidine

5.7 g (0.14 mol) of sodium hydride are suspended in 200 mL oftetrahydrofuran. 10 g (44 mmol) of 4-bromo-2-tert-butylaniline areadded, along with 200 mL of dimethyl sulfoxide, added slowly. Themixture turns blue and, after 30 minutes, 13 mL (0.14 mol) of1,4-dibromobutane are added and the reaction medium is stirred at roomtemperature for 13 hours. The reaction medium is then poured intosaturated ammonium chloride solution and extracted with ethyl acetate,and the organic phase is then washed twice with water, dried and thenconcentrated to dryness. The residue is purified by chromatography onsilica gel (eluent: 90/10 heptane/ethyl acetate). 6.4 g of1-(4-bromo-2-tert-butylphenyl)pyrrolidine are obtained (yield=52%) inthe form of a thick yellow oil.

b) Preparation of 3-tert-butyl-4-pyrrolidinophenylboronic acid

In a manner similar to that of Example 1c, by reacting 4.7 g (17 mmol)of 1-(4-bromo-2-tert-butylphenyl)pyrrolidine with 8 mL of a 2.5Msolution of n-butyllithium and 6 mL (26 mmol) of triisopropyl borate,2.8 g of 3-tert-butyl-4-pyrrolidinophenylboronic acid are obtained(yield=66%).

c) Preparation of ethyl3″-tert-butyl-4′-hydroxy-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 1d, by reacting 1 g of ethyl3′-bromo-4′-hydroxy-biphenyl-4-carboxylate (3 mmol) with 1.2 g of3-tert-butyl-4-pyrrolidinophenylboronic acid (4.5 mmol) in the presenceof 5 mL of 2M potassium carbonate (10 mmol) and 360 mg oftetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄), 900 mg of ethyl3″-tert-butyl-4′-hydroxy-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=63%) in the form of a yellow solid.

d) Preparation of ethyl3″-tert-butyl-4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 2a, by reacting 123 mg of ethyl3″-tert-butyl-4′-hydroxy-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate(0.27 mmol) with 110 mg (0.34 mmol) of caesium carbonate and 80 μL of1-bromo-4-(tert-butyldimethylsilanyloxy)butane (0.30 mmol), 170 mg ofethyl3″-tert-butyl-4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=97%) in the form of an oil.

e) Synthesis of ethyl3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 2b, by reacting 170 mg (0.26mmol) of ethyl3″-tert-butyl-4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylatewith 200 μL of a 1M solution of tetrabutylammonium fluoride, 100 mg ofethyl3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=71%) in the form of a white solid.

¹H NMR (CDCl₃-400 MHz): 1.43 (t, J=7.5 Hz, 3H); 1.47 (s, 9H); 1.64-1.71(m, 2H); 1.85-1.96 (m, 2H); 2.10-2.25 (m, 4H); 3.03 (m, 4H); 3.64 (m,2H); 4.09 (t, J=6.1 Hz, 2H); 4.41 (t, J=7.5 Hz, 2H); 7.07 (d, J=8.0 Hz,1H); 7.30 (s, 2H); 7.56-7.65 (m, 3H); 7.67 (d, J=8.2 Hz, 2H); 8.10 (d,J=8.2 Hz, 2H).

Example 19 Synthesis of3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 100 mg of ethyl3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate(0.18 mmol) with 0.3 mL of 1N sodium hydroxide solution. 50 mg of3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=56%) in the form of a white solid (m.p.=206°C.).

¹H NMR (DMSO, 400 MHz): 1.42 (s, 9H); 1.51 (m, 2H); 1.72 (m, 2H); 1.9(s, 4H); 3.4 (m, 2H); 4 (m, 2H); 7.2 (d, 1H, J=8.6 Hz); 7.4 (d, 1H,J=9.9 Hz); 7.45 (d, J=8.2 Hz); 7.55 (s); 7.63 (s, 1H); 7.67 (d, 1H,J=7.34 Hz); 7.8 (d, 2H, J=8.45 Hz); 7.97 (d, 2H, J=8.4 Hz).

Example 20 Synthesis of ethyl4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylate

a) Preparation of 1-(4-Bromo-2-trifluoromethylphenyl)pyrrolidine

In a manner similar to that of Example 18a, by reacting 40 g of4-bromo-2-trifluoromethylphenylamine (0.167 mol) with 16.6 g of sodiumhydride (0.42 mol) and 49.7 mL of 1,4-dibromobutane (0.42 mol), 8.5 g of1-(4-bromo-2-trifluoromethylphenyl)pyrrolidine (yield=17%) are obtainedin the form of a yellow oil.

b) Preparation of 4-pyrrolidino-3-trifluoromethylphenylboronic acid

In a manner similar to that of Example 1c, by reacting 2.3 g (7.9 mmol)of 1-(4-bromo-2-trifluoromethylphenyl)pyrrolidine with 3.8 mL of a 2.5Msolution of n-butyllithium and 2.7 mL of triisopropyl borate (12 mmol),2 g of 4-pyrrolidino-3-trifluoromethylphenylboronic acid are obtained(yield=100%) in the form of a beige-colored solid.

c) Preparation of ethyl3′-bromo-4′-[4-(tert-butyldimethylsilanyloxy)butoxy]biphenyl-4-carboxylate;

In a manner similar to that of Example 2a, by reacting 2 g of ethyl3′-bromo-4′-hydroxy-biphenyl-4-carboxylate (6 mmol) with 2.4 g (7.5mmol) of caesium carbonate and 1.78 mL of1-bromo-4-(tert-butyldimethylsilanyloxy)butane (6.7 mmol), 2.8 g ofethyl3′-bromo-4′-[4-(tert-butyldimethylsilanyloxy)butoxy]biphenyl-4-carboxylateare obtained (yield=97%) in the form of an oil.

d) Preparation of ethyl4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-4″-pyrrolidin-1-yl-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 1d, by reacting 500 mg of ethyl3′-bromo-4′-[4-(tert-butyldimethylsilanyloxy)butoxy]biphenyl-4-carboxylate(1.2 mmol) with 450 mg of 4-pyrrolidino-3-trifluoromethylphenylboronicacid (1.7 mmol) in the presence of 1.5 mL of 2M potassium carbonate (3mmol) and 40 mg of tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄),400 mg of ethyl4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-4″-pyrrolidin-1-yl-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=56%) in the form of a colorless oil.

e) Synthesis of ethyl4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 2b, by reacting 400 mg of ethyl4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-4″-pyrrolidin-1-yl-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylate(0.6 mmol) with 0.75 mL of a 1N solution of tetrabutylammonium fluoride,318 mg of ethyl4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=97%) in the form of a colorless oil.

¹H NMR (CDCl₃-400 MHz): 1.43 (t, J=7.5 Hz, 3H); 1.55 (m, 2H); 1.68-1.73(m, 2H); 1.93 (m, 8H); 3.42 (m, 2H); 4.08 (t, J=6.2 Hz, 2H); 4.41 (t,J=7.5 Hz, 2H); 4.43 (bs, 1H); 7.13 (d, J=8.7 Hz, 1H); 7.21 (d, J=8.7 Hz,1H); 7.67-7.73 (m, 3H); 7.85 (d, J=8.2 Hz, 2H); 7.87 (s, 1H); 7.99 (d,J=8.2 Hz, 2H).

Example 21 Synthesis of4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 318 mg of ethyl4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylatewith 6 mL of 1N sodium hydroxide solution, 75 mg of4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=25%) in the form of a white solid (m.p.=237°C.).

¹H NMR (DMSO, 400 MHz): 1.55 (m, 2H); 1.73 (m, 2H); 1.93 (m, 8H); 3.42(m, 2H); 4.08 (t, J=6.2 Hz, 2H); 4.43 (bs, 1H); 7.13 (d, J=8.7 Hz, 1H);7.21 (d, J=8.7 Hz, 1H); 7.67-7.73 (m, 3H); 7.85 (d, J=8.2 Hz, 2H); 7.87(s, 1H); 7.99 (d, J=8.2 Hz, 2H); 12.9 (bs, 1H).

Example 22 Synthesis of ethyl3″-tert-butyl-4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate

a) Preparation of Ethyl3″-tert-butyl-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 1d, by reacting 500 mg of ethyl3′-bromo-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]biphenyl-4-carboxylateobtained in Example 9b (1.2 mmol) with 380 mg of3-tert-butyl-4-pyrrolidinophenylboronic acid (1.5 mmol) obtained inExample 17b in the presence of 1.3 mL of 2M potassium carbonate (2.6mmol) and 35 mg of tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄),550 mg of ethyl3″-tert-butyl-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=89%) in the form of a yellow oil.

b) Synthesis of ethyl3″-tert-butyl-4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 2b, by reacting 550 mg of ethyl3″-tert-butyl-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate(0.9 mmol) with 1.1 mL of a 1N solution of tetrabutylammonium fluoride,260 mg of ethyl3″-tert-butyl-4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=58%) in the form of a yellow oil.

¹H NMR (CDCl₃-400 MHz): 1.43 (t, J=7.5 Hz, 3H); 1.47 (s, 9H); 2.05 (m,2H); 2.10-2.25 (m, 4H); 3.03 (m, 4H); 3.81 (m, 2H); 4.17 (t, J=5.7 Hz,2H); 4.41 (t, J=7.5 Hz, 2H); 7.07 (d, J=8.0 Hz, 1H); 7.30 (s, 2H);7.56-7.65 (m, 3H); 7.67 (d, J=8.2 Hz, 2H); 8.10 (d, J=8.2 Hz, 2H).

Example 23 Synthesis of3″-tert-butyl-4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 260 mg of ethyl3″-tert-butyl-4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate(0.5 mmol) with 5 mL of 1N sodium hydroxide solution, 120 mg of3″-tert-butyl-4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=48%) in the form of a white solid (m.p.=230°C.).

HPLC Waters Atlantis C₁₈, 5 microns, 2×150 mm, mobile phase: A(CH₃CN/0.1 v/v HCO₂H); B (H₂O/0.1 v/v HCO₂H), Flow rate: 0.5 mL/minutes.Gradient: 0 min: 90% B, 0-20 min: 90-5% B, 20-30 min: 5% B; retentiontime: 13.2 min, purity: 97.8%, MS (ESI) m/z 474.3 (M+H)⁺.

Example 24 Synthesis of ethyl3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate

a) Preparation of ethyl4′-(2-acetoxyethoxy)-3″-tert-butyl-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 1d, by reacting 800 mg of ethyl3′-bromo-4′-(2-acetoxyethoxy)biphenyl-4-carboxylate obtained in Example13a (2 mmol) with 730 mg of 3-tert-butyl-4-pyrrolidinophenylboronic acid(2.9 mmol) obtained in Example 18b in the presence of 2.6 mL of 2Mpotassium carbonate (5.2 mmol) and 70 mg oftetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄), 500 mg of ethyl4′-(2-acetoxyethoxy)-3″-tert-butyl-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=47%) in the form of a yellow oil.

b) Synthesis of ethyl3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 14a, by reacting 110 mg of ethyl4′-(2-acetoxyethoxy)-3″-tert-butyl-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate(0.2 mmol) with 2 mL of a 1% solution of potassium carbonate in ethanol,40 mg of ethyl3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=39%) in the form of a white solid (m.p.=193° C.).

¹H NMR (DMSO, 400 MHz): 1.40 (t, 3H); 1.46 (m, 4H); 1.54 (s, 9H); 1.9(bs, 4H); 3.0 (bs, 3H); 3.9 (bs, 2H); 4.15 (m, 2H); 4.40 (m, 2H); 7.1(d, J=8.6 Hz, 1H); 7.4 (d, J=9.9 Hz, 1H); 7.45 (d, J=8.2 Hz, 1H); 7.55(s, 1H); 7.63 (s, 1H); 7.67 (d, J=7.34 Hz, 1H); 7.80 (d, J=8.45 Hz, 2H);7.97 (d, J=8.4 Hz, 2H).

Example 25 Synthesis of3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 6b, by reacting 500 mg (0.9 mmol)of ethyl4′-(2-acetoxyethoxy)-3″-tert-butyl-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylatewith 300 mg (8 mmol) of sodium hydroxide, 242 mg of3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=55%) in the form of a white solid (m.p.=223°C.).

¹H NMR (DMSO, 400 MHz): 1.43 (s, 9H); 1.90 (m, 4H); 3.0 (m, 4H); 3.73(d, J=4.7 Hz, 2H); 4.1 (m, 2H); 4.7 (s, 1H); 7.2 (d, 1H, J=8.6 Hz); 7.48(m, 2H); 7.59 (d, J=1.6 Hz, 1H); 7.64 (d, J=1.1 Hz, 1H); 7.68 (dd, J=2Hz, 7.8 Hz, 1H); 7.82 (d, J=8.3 Hz, 2H); 7.99 (d, J=8.4 Hz, 2H).

Example 26 Synthesis of4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid

a) Preparation of 4-pyrrolidinophenylboronic acid

In a manner similar to that of Example 1c, by reacting 8.6 g (38 mmol)of 4-bromophenyl-1-pyrrolidine with 18 mL of a 2.5M solution ofn-butyllithium and 13 mL of triisopropyl borate (57 mmol), 5 g of4-pyrrolidinophenylboronic acid are obtained (yield=69%) in the form ofa beige-colored solid.

b) Preparation of ethyl4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 1d, by reacting 520 mg of ethyl3′-bromo-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]biphenyl-4-carboxylateobtained in Example 8b (1 mmol) with 290 mg of4-pyrrolidinophenylboronic acid (1.5 mmol) in the presence of 1.3 mL of2M potassium carbonate (2.6 mmol) and 35 mg oftetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄), 170 mg of ethyl4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=30%) in the form of a yellow oil.

c) Preparation of ethyl4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 2b, by reacting 170 mg of ethyl4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate(0.3 mmol) with 0.4 mL of a 1N solution of tetrabutylammonium fluoride,70 mg of ethyl4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=52%) in the form of a yellow oil.

d) Synthesis of4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 70 mg of ethyl4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate(0.16 mmol) with 1.6 mL of 1N sodium hydroxide solution, 10 mg of4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=15%) in the form of a white solid (m.p.=195°C.).

HPLC Thermo Aquasil C₁₈, 3 microns, 2×150 mm, mobile phase: A (CH₃CN/0.1v/v HCO₂H); B (H₂O/0.1 v/v HCO₂H), Flow rate: 0.5 mL/minutes. Gradient:0 min: 90% B, 0-20 min: 90-5% B, 20-30 min: 5% B; retention time: 14.77min, purity: 93%, MS (ESI) m/z 418.2 (M+H)⁺.

Example 27 Synthesis of3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 300 mg of ethyl3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylateobtained in Example 1d (0.67 mmol) with 7 mL of 1N sodium hydroxidesolution, 236 mg of3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=84%) in the form of a white solid (m.p.=190°C.).

¹H NMR (DMSO, 400 MHz): 1.06 (t, J=7.4 Hz, 6H); 1.46 (s, 9H); 2.84 (bs,2H); 2.94 (bs, 2H); 7.05 (d, J=8.5 Hz, 1H); 7.31-7.47 (m, 2H); 7.54-7.62(m, 3H); 7.78 (d, J=6.7 Hz, 2H); 7.97 (d, J=6.7 Hz, 2H); 9.82 (s, 1H);12.90 (bs, 1H).

Example 28 Synthesis of ethyl4″-diethylamino-4′-hydroxy-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylate

a) Preparation of (4-bromo-2-trifluoromethylphenyl)diethylamine

In a manner similar to that of Example 1b, by reacting 10 g of4-bromo-2-trifluoromethylphenylamine (41 mmol) with 5 g (125 mmol) of60% sodium hydride and 10 mL (125 mmol) of ethyl iodide, 7 g of(4-bromo-2-trifluoromethylphenyl)diethylamine are obtained (yield=60%)in the form of a yellow oil.

b) Preparation of 4-diethylamino-3-trifluoromethylphenylboronic acid

In a manner similar to that of Example 1c, by reacting 5 g of(4-bromo-2-trifluoromethylphenyl)diethylamine with 8.1 mL of a 2.5 Msolution of n-butyllithium and 5.8 mL of triisopropyl borate, 4.3 g of4-diethylamino-3-trifluoromethylphenylboronic acid are obtained(yield=100%) in the form of a thick orange oil.

c) Synthesis of ethyl4″-diethylamino-4′-hydroxy-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 1d, by reacting 3.5 g of ethyl3′-bromo-4′-hydroxy-biphenyl-4-carboxylate (10.9 mmol) with 4.3 g of4-diethylamino-3-trifluoromethylphenylboronic acid (16.4 mmol) in thepresence of 14.3 mL of 2M potassium carbonate solution (28.5 mmol) and380 mg of tetrakis(triphenylphosphine)palladium (0.3 mmol), 1.4 g ofethyl4″-diethylamino-4′-hydroxy-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=28%) in the form of a white solid (m.p.=170° C.).

¹H NMR (DMSO, 400 MHz): 0.97 (t, J=7.1 Hz, 6H); 1.44 (t, J=7.6H, 3H);2.98 (q, J=7.1 Hz, 4H); 5.49 (s, 1H); 7.09 (d, J=8.4 Hz, 1H); 7.60 (m,2H); 7.69 (d, J=2.3 Hz, 1H); 7.81 (d, J=8.4 Hz, 2H); 7.93 (m, 2H); 7.97d, J=8.4 Hz, 2H).

Example 29 Synthesis of4″-diethylamino-4′-hydroxy-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 200 mg of ethyl4″-diethylamino-4′-hydroxy-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylate(0.44 mmol) with 4 mL of 1N sodium hydroxide solution, 100 mg of4″-diethylamino-4′-hydroxy-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=50%) in the form of a white solid (m.p.=195°C.).

¹H NMR (DMSO, 400 MHz): 0.97 (t, J=7.1 Hz, 6H); 2.98 (q, J=7.1 Hz, 4H);7.09 (d, J=8.4 Hz, 1H); 7.60 (m, 2H); 7.69 (d, J=2.3 Hz, 1H); 7.81 (d,J=8.4 Hz, 2H); 7.93 (m, 2H); 7.97 d, J=8.4 Hz, 2H); 10.05 (s, 1H); 12.90(bs, 1H).

Example 30 Synthesis of3″-tert-butyl-4″-diethylamino-4′-(4-isopropylaminobutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

a) Preparation of ethyl3″-tert-butyl-4″-diethylamino-4′-(4-oxobutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate

20 mL of dichloromethane placed in a three-necked flask are cooled to−78° C. and 0.3 mL of oxalyl chloride are added, followed by addition of0.54 mL of dimethyl sulfoxide diluted in 4 mL of dichloromethane. Thereaction medium is stirred at −78° C. for 30 minutes.

900 mg of ethyl3″-tert-butyl-4″-diethylamino-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylateobtained in Example 2b (1.7 mmol), dissolved in 55 mL of dichloromethanein the presence of 1 equivalent of triethylamine are added. The reactionmedium is stirred at −78° C. for 1 hour and then at room temperature for12 hours.

The reaction is stopped by adding 100 mL of saturated ammonium chloridesolution and then extracted with dichloromethane. The organic phase iswashed twice with water, dried over magnesium sulfate, filtered andconcentrated. The residue obtained is chromatographed on silica gel(70/30 heptane/ethyl acetate). 720 mg of ethyl3″-tert-butyl-4″-diethylamino-4′-(4-oxobutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=78%) in the form of a yellow oil.

b) Preparation of ethyl3″-tert-butyl-4″-diethylamino-4′-(4-isopropylaminobutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate

720 mg of aldehyde ethyl3″-tert-butyl-4″-diethylamino-4′-(4-oxobutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate(1.3 mmol) are dissolved in 15 mL of methanol under a nitrogenatmosphere. 0.6 mL of isopropylamine are then added. The reaction mediumis stirred at room temperature for 1 hour 15 minutes. 94 mg of sodiumcyanoborohydride are then added to the reaction medium with stirring.The medium is stirred for 3 days. The reaction is stopped by adding 5 mLof water and then extracted with ethyl acetate. The organic phases arecombined and dried over magnesium sulfate. The solvents are evaporatedoff and the residue is precipitated from 8 mL of heptane and filteredthrough a sinter funnel. 178 mg of ethyl3″-tert-butyl-4″-diethylamino-4′-(4-isopropylaminobutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=24%) in the form of a white solid.

c) Synthesis of3″-tert-butyl-4″-diethylamino-4′-(4-isopropylaminobutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 190 mg of ethyl3″-tert-butyl-4″-diethylamino-4′-(4-isopropylaminobutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate(0.3 mmol) with 0.5 mL of 1N sodium hydroxide solution, 45 mg of3″-tert-butyl-4″-diethylamino-4′-(4-isopropylaminobutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=25%) in the form of a white solid.

¹H NMR (CD₃OD, 400 MHz): 1.11 (t, 6H); 1.26 (d, 6H); 1.52 (s, 9H); 1.84(m, 2H); 1.90 (m, 2H); 2.98 (s, 4H); 3.2 (m, 1H); 3.3 (m, 2H); 4.13 (t,2H); 7.19 (d, J=8.54 Hz, 1H); 7.36 (s, 1H); 7.42 (s, 1H); 7.61 (s, 1H);7.65 (s, 2H); 7.72 (d, J=8.36 Hz, 2H); 8.08 (d, J=8.35 Hz, 2H).

Example 31 Synthesis of3″-tert-butyl-4′-(4-isopropylaminobutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid

a) Preparation of ethyl3″-tert-butyl-4′-(4-oxobutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 30a, by reacting 900 mg of ethyl3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylateobtained in Example 18e with 0.3 mL of oxalyl chloride, 0.54 mL of DMSOand 0.25 mL of triethylamine, 700 mg of ethyl3″-tert-butyl-4′-(4-oxobutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=78%) in the form of a yellow oil.

b) Preparation of ethyl3″-tert-butyl-4′-(4-isopropylaminobutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 30b, by reacting 700 g of ethyl3″-tert-butyl-4′-(4-oxobutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylatewith 0.6 mL of isopropylamine and 94 mg of sodium cyanoborohydride, 228mg of ethyl3″-tert-butyl-4′-(4-isopropylaminobutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=24%) in the form of a white solid.

c) Synthesis of3″-tert-butyl-4′-(4-isopropylaminobutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 190 mg of ethyl3″-tert-butyl-4′-(4-isopropylaminobutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate(0.3 mmol) with 2 mL of 1N sodium hydroxide solution, 45 mg of3″-tert-butyl-4″-diethylamino-4′-(4-isopropylaminobutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=25%) in the form of a white solid.

HPLC Waters Atlantis C₁₈, 5 microns, 2×150 mm, mobile phase: A(CH₃CN/0.05 v/v CF₃CO₂H); B (H₂O/0.05 v/v CF₃CO₂H), Flow rate: 1mL/minutes. Gradient: 0 min: 90% B, 0-20 min: 90-10% B, 20-30 min: 10%B; retention time: 17.5 min, purity: 98%, MS (ESI) m/z 541.3 (M+H)⁺.

Example 32 Synthesis of ethyl3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate

a) Preparation of ethyl3″-tert-butyl-4″-diethylamino-4′-trifluoromethanesulfonyloxy[1,1′;3′,1″]terphenyl-4-carboxylate

g of ethyl3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylateobtained in Example 1d (2.5 mmol) are dissolved at room temperature in22.4 mL of dichloromethane and the temperature of the reaction medium isthen lowered to 0° C.; 112 mg of dimethylaminopyridine are added,followed by addition of 0.88 mL of triethylamine (6 mmol) and dropwiseaddition of 0.5 mL of triflic anhydride (3 mmol). The temperature israised to room temperature and the reaction medium is stirred for 20minutes. The reaction is stopped by adding 30 mL of water and thenextracted with 30 mL of dichloromethane. The organic phases are washedwith 60 mL of water and then dried over sodium sulfate. The solvents areevaporated off and the residue is then purified by chromatography onsilica gel (eluent: heptane). 1.2 g of ethyl3″-tert-butyl-4″-diethylamino-4′-trifluoromethanesulfonyloxy[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=79%).

b) Preparation of ethyl3″-tert-butyl-4″-diethylamino-4′-vinyl[1,1′;3′,1″]terphenyl-4-carboxylate

g of ethyl3″-tert-butyl-4″-diethylamino-4′-trifluoromethanesulfonyloxy[1,1′;3′,1″]terphenyl-4-carboxylate(2 mmol) are dissolved at room temperature in 23 mL ofdimethylformamide, and 250 mg of LiCl (6 mmol) and 0.74 mL ofallyltributyltin (2.4 mmol) are then added. The reaction medium isheated and, at 40° C., 70 mg of dichlorobis(triphenylphosphine)palladium(0.1 mmol) are added and the reaction medium brought to 120° C. andstirred for 20 minutes. The reaction is stopped by adding 30 mL of waterand then extracted with 30 mL of ethyl acetate. The organic phases arewashed with 80 mL of water and then dried over magnesium sulfate. Thesolvents are evaporated off and the residue is then purified bychromatography on silica gel (eluent: heptane). 940 mg of ethyl3″-tert-butyl-4″-diethylamino-4′-vinyl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=100%).

c) Synthesis of ethyl3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate

8 g of ethyl3″-tert-butyl-4″-diethylamino-4′-vinyl[1,1′;3′,1″]terphenyl-4-carboxylate(17 mmol) are dissolved in 400 mL of THF with stirring and, under coldconditions (ice bath), 6.2 g of 9 borabicyclo[3.3.1]nonane (51 mmol) areadded and the ice bath is removed to raise the temperature of thereaction medium to room temperature, at which point the reaction mediumis stirred for 1 hour 30 minutes. The temperature of the reaction mediumis again reduced to 0° C., 52.8 mL of NaOH (53 mmol) are addedportionwise, and the medium is stirred for 10 minutes at 0° C.; 37.3 mLof H₂O₂ (426 mmol) are then added dropwise and the reaction medium iswarmed to room temperature and then stirred for 2 hours 30 minutes. Thereaction is stopped by adding 500 mL of ice-water and then extractedwith 500 mL of ethyl acetate. The organic phases are washed with 1 L ofwater and then dried over magnesium sulfate. The solvents are evaporatedoff and the residue is then purified by chromatography on silica gel(eluent: 7/3 heptane/ethyl acetate). 6.4 g of ethyl3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=75%).

¹H NMR (CDCl₃, 400 MHz): 1.13 (t, 6H); 1.44 (t, J=7.5 Hz, 3H); 1.50 (s,9H); 1.75-1.78 (m, 2H), 2.76 (t, 2H); 2.88 (bs, 2H); 2.97 (bs, 2H);3.51-3.56 (m, 2H); 4.41 (q, J=7.5 Hz, 2H); 7.19 (m, 1H); 7.32 (d, J=8Hz, 1H); 7.38-7.42 (m, 2H); 7.55-7.61 (m, 2H); 7.72 (d, J=8.4 Hz, 2H);8.11 (d, J=8.4 Hz, 2H). 1.09 (t, 6H); 1.5 (s, 9H); 1.7 (m, 2H), 2.75 (t,2H); 2.90-2.99 (m, 4H); 3.5 (t, 2H); 7.19 (d, 1H, J=7.0 Hz); 7.31 (d,1H, J=8 Hz); 7.42 (d, 2H, J=8 Hz); 7.56 (s, 2H); 7.76 (d, 2H, J=8.4 Hz);8.17 (d, 2H, J=8.4 Hz).

Example 33 Synthesis of3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 70 mg of ethyl3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate(0.14 mmol) with 0.2 mL of 1N sodium hydroxide solution, 64 mg of3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=94%) in the form of a white solid (m.p.=95°C.).

¹H NMR (CDCl₃, 400 MHz): 1.09 (t, 6H); 1.5 (s, 9H); 1.7 (m, 2H), 2.75(t, 2H); 2.90-2.99 (m, 4H); 3.5 (t, 2H); 7.19 (d, 1H, J=7.0 Hz); 7.31(d, 1H, J=8 Hz); 7.42 (d, 2H, J=8 Hz); 7.56 (s, 2H); 7.76 (d, 2H, J=8.4Hz); 8.17 (d, 2H, J=8.4 Hz).

Example 34 Synthesis of ethyl3″-tert-butyl-4″-diethylamino-4′-(2,3-dihydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate

150 mg of ethyl3″-tert-butyl-4″-diethylamino-4′-vinyl[1,1′;3′,1″]terphenyl-4-carboxylateobtained in Example 32b are dissolved in 10 mL of dichloromethane undera nitrogen atmosphere. 45 mg of N-methylmorpholine are added to thereaction medium, and 0.5 mL of a commercial 2.5% solution of osmiumtetroxide in water is then added dropwise and the reaction medium isstirred at room temperature for 3 hours. The reaction is then stopped byadding 10 mL of water and extracted with dichloromethane. The organicphase is washed with water, dried over magnesium sulfate and filteredthrough a sinter funnel. The solvent is evaporated off and the residueobtained is purified by chromatography on silica (eluent: 7/3heptane/ethyl acetate). 20 mg of ethyl3″-tert-butyl-4″-diethylamino-4′-(2,3-dihydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylateare obtained in the form of a white solid.

¹H NMR (CDCl₃, 400 MHz): 1.12 (t, 6H); 1.43 (t, J=7.5 Hz, 3H); 1.57 (s,9H); 2.87 (t, 2H); 2.9 (bs, 2H); 2.97 (bs, 2H); 3.33-3.52 (m, 2H); 3.77(m, 1H); 4.42 (q, J=7.5 Hz, 2H); 7.18 (d, 1H, J=8.0 Hz); 7.31 (d, J=8.0Hz, 1H); 7.39 (d, J=2 Hz, 1H); 7.47 (d, J=7.8 Hz); 7.57-7.60 (m, 2H);7.71 (d, J=8.4 Hz, 2H); 8.12 (d, J=8.4 Hz, 2H).

Example 35 Synthesis of3″-tert-butyl-4″-diethylamino-4′-(2,3-dihydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 70 mg of ethyl3″-tert-butyl-4″-diethylamino-4′-(2,3-dihydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate(0.14 mmol) with 0.2 mL of 1N sodium hydroxide solution, 58 mg of3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=86%) in the form of a white solid (m.p.=130°C.).

¹H NMR (CDCl₃, 400 MHz): 1.09 (t, 6H); 1.49 (s, 9H); 2.83 (t, 2H); 2.92(m, 4H); 3.33-3.52 (m, 2H); 3.77 (m, 1H); 7.18 (d, J=7.9 Hz, 1H); 7.31(d, J=8 Hz, 1H); 7.42 (d, J=8 Hz, 2H); 7.56 (s, 2H); 7.76 (d, J=8.4 Hz,2H); 8.17 (d, J=8.4 Hz, 2H).

Example 36 Synthesis of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate

a) Preparation of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-trifluoromethanesulfonyloxy[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 32a, by reacting 7 g (58.5 mmol)of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylateobtained in Example 4d with 3.85 g (38 mmol, 5.3 mL) of triethylamineand 0.70 g (5.7 mmol) of 4-dimethylaminopyridine and 5.16 g (18 mmol,3.1 mL) of triflic anhydride, 2.56 g of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-trifluoromethanesulfonyloxy[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=28%) in the form of a yellow oil.

b) Preparation of ethyl4″-(acetylethylamino)-4′-allyl-3″-tert-butyl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 32b, by reacting 2.5 g (4.3 mmol)of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-trifluoromethanesulfonyloxy[1,1′;3′,1″]terphenyl-4-carboxylatewith 540 mg (12.7 mmol) of lithium chloride and 1.66 g (5.0 mmol) ofallyltributyltin and 148 mg (0.2 mmol) ofdichlorobis(triphenylphosphine)palladium, 1.67 g of ethyl4″-(acetylethylamino)-4′-allyl-3″-tert-butyl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=80%) in the form of a yellow oil.

c) Synthesis of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 32c, by reacting 0.2 g (0.41mmol) of ethyl4″-(acetylethylamino)-4′-allyl-3″-tert-butyl[1,1′;3′,1″]terphenyl-4-carboxylatewith 150 mg (1.24 mmol) of 9-borabicyclo[3.3.1]nonane, followed byaddition of 1.25 mL (1.28 mmol) of 1N sodium hydroxide solution and 1 g(10.3 mmol) of hydrogen peroxide, 205 mg of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=100%) in the form of a colorless oil.

¹H NMR (CDCl₃, 400 MHz): 1.28 (t, J=7.2 Hz, 3H); 1.43 (s, 9H); 1.46 (t,3H); 1.78 (m, 2H); 1.88 (s, 3H); 2.76 (t, J=7.2 Hz, 2H); 2.94 (m, 1H);3.57 (t, J=6.4 Hz, 2H); 4.43 (t, J=7.2 Hz, 2H); 4.45 (m, 1H); 7.07 (d,J=8.0 Hz, 1H); 7.23 (dd, J₁=2 Hz, J₂=8.0 Hz, 1H); 7.45 (d, J=8.0 Hz,1H); 7.52 (d, J=2.0 Hz, 1H); 7.56 (d, J=2.0 Hz, 1H); 7.62 (dd, J₁=2.0Hz, J₂=8.0 Hz, 1H); 7.73 (d, J=8.4 Hz, 2H); 8.12 (d, J=8.4 Hz, 2H).

Example 37 Synthesis of4″-(acetylethylamino)-3″-tert-butyl-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 200 mg of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate(0.4 mmol) with 1 mL of 1N sodium hydroxide solution, 45 mg of4″-(acetylethylamino)-3″-tert-butyl-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=23%) in the form of a white solid (m.p.=209°C.).

¹H NMR (CDCl₃, 400 MHz): 1.21 (t, J=7.2 Hz, 3H); 1.41 (s, 9H); 1.78 (m,2H); 1.88 (s, 3H); 2.75 (t, J=7.2 Hz, 2H); 2.94 (m, 1H); 3.56 (t, J=6.4Hz, 2H); 4.45 (m, 1H); 7.07 (d, J=8.0 Hz, 1H); 7.23 (dd, J₁=2 Hz, J₂=8.0Hz, 1H); 7.45 (d, J=8.0 Hz, 1H); 7.52 (d, J=2.0 Hz, 1H); 7.56 (d, J=2.0Hz, 1H); 7.62 (dd, J₁=2.0 Hz, J₂=8.0 Hz, 1H); 7.73 (d, J=8.4 Hz, 2H);8.18 (d, J=8.4 Hz, 2H).

Example 38 Synthesis of ethyl3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate

a) Preparation of ethyl4′-(3-bromopropyl)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate

6.4 g of ethyl3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylateobtained in Example 32c (13 mmol) are dissolved in 128 mL of diethylether. The dissolution is performed under cold conditions (0° C.), and11.4 mL of trioctylphosphine are then added (26 mmol) followed byaddition of a solution of 8.5 g of carbon tetrabromide (26 mmol)dissolved in 10 volumes of Et₂O added dropwise. The reaction medium isstirred at 0° C. for 30 minutes and then for 1 hour 30 minutes at roomtemperature. The reaction is stopped by adding 100 mL of water and thenextracted with 100 mL of ethyl acetate. The organic phases are washedwith 400 mL of water and then dried over magnesium sulfate. The solventsare evaporated off and the residue is then purified by chromatography onsilica gel (eluent: 9/1 heptane/ethyl acetate). 6 g of ethyl4′-(3-bromopropyl)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=83%) in the form of a thick brown oil.

b) Synthesis of ethyl3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate

600 mg of ethyl4′-(3-bromopropyl)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate(1.1 mmol) are dissolved in 12 mL of ethanol at room temperature, and0.76 mL of cyclopropylamine (11 mmol) are then added. The medium isbrought to reflux, and stirred for 24 hours. After concentrating thereaction mixture, the residue is purified by chromatography on silicagel.

(eluent: 95/5 dichloromethane/methanol). 300 mg of ethyl3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=53%).

¹H NMR (CDCl₃, 400 MHz): 0.66 (d, J=6.7 Hz, 2H); 0.95 (d, J=7.3 Hz, 2H);1.12 (t, J=7.2 Hz, 6H); 1.43 (t, J=7.5 Hz, 3H); 1.49 (s, 9H); 2.01-2.08(m, 2H); 2.30-2.34 (m, 1H); 2.76 (t, J=7.7 Hz, 2H); 2.83 (t, J=7.7 Hz,2H); 2.90 (bs, 2H); 2.98 (bs, 2H); 4.42 (q, J=7.5 Hz, 2H); 7.16 (m, 1H);7.28-7.34 (m, 2H); 7.43 (d, J=8.0 Hz, 1H); 7.52-7.56 (m, 2H); 7.68 (dd,J₁=1.9 Hz, J₂=6.8 Hz, 2H); 8.10 (d, J₁=1.9 Hz, J₂=6.8 Hz, 2H).

Example 39 Synthesis of3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 300 mg of ethyl3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate(0.57 mmol) with 2 mL of 1N sodium hydroxide solution, 50 mg of3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=18%) in the form of a white solid (m.p.=189°C.).

¹H NMR (CD₃OD, 400 MHz): 0.62 (m, 2H); 0.72 (m, 2H); 1.14 (t, J=7.17 Hz,6H); 1.52 (s, 9H); 1.83 (m, 2H); 2.42 (m, 1H); 2.81 (m, 4H); 2.92 (m,2H); 3.05 (m, 2H); 7.22 (dd, J₁=2.01 Hz, J₂=8.04 Hz, 1H); 7.24-7.44 (m,3H); 7.49 (5, 1H); 7.61-7.67 (m, 3H); 8.03 (d, J=8.39 Hz, 2H).

Example 40 Synthesis of ethyl3″-tert-butyl-4′-(3-cyclopentylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 38b, by reacting 600 mg of ethyl4′-(3-bromopropyl)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate(1.1 mmol) with 1.1 mL of cyclopentylamine (11 mmol), 560 mg of ethyl3″-tert-butyl-4′-(3-cyclopentylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=93%) in the form of an orange-colored oil.

¹H NMR (CDCl₃, 400 MHz): 1.14 (t, J=8.2 Hz, 6H); 1.46 (t, J=7.5 Hz, 3H);1.49 (s, 9H); 1.52-1.54 m, 2H); 1.75-1.81 (m, 2H); 1.91-1.98 (m, 2H);2.07-2.13 (m, 2H); 2.73 (t, J=8.2 Hz, 4H); 2.94 (bs, 2H); 3.0 (bs, 2H);3.20 (m, 1H); 4.41 (q, J=7.5 Hz, 2H); 5.2 (bs, 1H); 7.15 (m, 1H);7.29-7.32 (m, 2H); 7.44 (d, J=8.0 Hz, 1H); 7.51-7.55 (m, 2H); 7.67 (dd,J₁=1.8 Hz, J₂=6.7 Hz, 2H); 8.09 (d, J₁=1.8 Hz, J₂=6.7 Hz, 2H).

Example 41 Synthesis of3″-tert-butyl-4′-(3-cyclopentylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 300 mg of ethyl3″-tert-butyl-4′-(3-cyclopentylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate(0.57 mmol) with 2 mL of 1N sodium hydroxide solution, 300 mg of3″-tert-butyl-4′-(3-cyclopentylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=56%) in the form of a white solid (m.p.=255°C.).

¹H NMR (CD₃OD, 400 MHz): 1.14 (t, J=7.18 Hz, 6H); 1.52 (s, 9H);1.45-1.95 (m, 8H); 2.03 (m, 2H); 2.82 (t, J=8.06 Hz, 4H); 2.94 (m, 2H);3.05 (m, 2H); 7.24 (d, J=2.08 Hz, 2H); 7.40 (m, 2H); 7.49 (d, J=1.94 Hz,1H); 7.62 (m, 3H); 8.0 (d, J=8.4 Hz, 2H).

Example 42 Synthesis of ethyl3″-tert-butyl-4′-(3-cyclohexylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 38b, by reacting 600 mg of ethyl4′-(3-bromopropyl)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate(1.1 mmol) with 1.25 mL of cyclohexylamine (11 mmol), 620 mg of ethyl3″-tert-butyl-4′-(3-cyclohexylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=100%) in the form of an orange-colored oil.

¹H NMR (CDCl₃, 400 MHz): 1.12 (t, J=7.8 Hz, 6H); 1.46 (t, J=7.5 Hz, 3H);1.49 (s, 9H); 1.52-1.54 m, 2H); 1.71-1.81 (m, 4H); 1.91-1.98 (m, 2H);2.00-2.05 (m, 2H); 2.71 (m, 4H); 2.90 (bs, 2H); 2.90 m, 1H); 2.97 (bs,2H); 3.20 (m, 1H); 4.2 (bs, 1H); 4.41 (q, J=7.5 Hz, 2H); 7.15 (m, 1H);7.28-7.33 (m, 2H); 7.45 (d, J=7.8 Hz, 1H); 7.52-7.56 (m, 2H); 7.67 (dd,J₁=1.8 Hz, J₂=6.7 Hz, 2H); 8.10 (dd, J₁=1.8 Hz, J₂=6.7 Hz, 2H).

Example 43 Synthesis of3″-tert-butyl-4′-(3-cyclohexylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 600 mg of ethyl3″-tert-butyl-4′-(3-cyclohexylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate(1.2 mmol) with 3 mL of 1N sodium hydroxide solution, 400 mg of3″-tert-butyl-4′-(3-cyclohexylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=56%) in the form of a white solid (m.p.=253°C.).

¹H NMR (CD₃OD, 400 MHz): 1.13 (t, J=7.13 Hz, 6H); 1.52 (s, 9H);1.58-1.93 (m, 12H); 2.45 (m, 1H); 2.52 (t, J=7.66 Hz, 2H); 2.73 (t,J=7.67 Hz, 2H); 2.52 (m, 2H); 3.05 (m, 2H); 7.22 (dd, J₁=2.02 Hz,J₂=7.98 Hz, 1H); 7.39 (m, 3H); 7.47 (d, J=1.90 Hz, 1H); 7.61 (m, 3H);8.02 (d, J=8.28 Hz, 2H).

Example 44 Synthesis of ethyl3″-tert-butyl-4′-(3-tert-butylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 38b, by reacting 600 mg of ethyl4′-(3-bromopropyl)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate(1.1 mmol) with 1.06 mL of tert-butylamine (11 mmol), 500 mg of ethyl3″-tert-butyl-4′-(3-tert-butylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=92%) in the form of an orange-colored oil.

¹H NMR (CDCl₃, 400 MHz): 1.12 (t, J=7.2 Hz, 6H); 1.43 (t, J=7.5 Hz, 3H);1.44 (s, 9H); 1.48 (s, 9H); 2.37-2.41 (m, 2H); 2.68-2.74 (m, 4H); 2.85(bs, 2H); 2.95 (bs, 2H); 4.40 (q, J=7.5 Hz, 2H); 7.12 (m, 1H); 7.28-7.31(m, 2H); 7.44 (d, J=8.0 Hz, 1H); 7.50-7.53 (m, 2H); 7.63 (d, J=6.8 Hz,2H); 8.07 (d, J=6.8 Hz, 2H); 8.88 (bs, 1H).

Example 45 Synthesis of3″-tert-butyl-4′-(3-tert-butylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 480 mg of ethyl3″-tert-butyl-4′-(3-tert-butylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate(0.8 mmol) with 3 mL of 1N sodium hydroxide solution, 250 mg of3″-tert-butyl-4′-(3-tert-butylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=55%) in the form of a white solid (m.p.=273°C.).

¹H NMR (CDCl₃, 400 MHz): 1.10 (t, J=7.2 Hz, 6H); 1.41 (s, 9H); 1.46 (s.9H); 2.31 (m, 2H); 2.64 (m, 2H); 2.72 (m, 2H); 2.89 (m, 2H); 2.97 (m,2H); 7.11 (m, 2H); 7.21 (d, J=8.0 Hz, 1H); 7.28 (m, 2H); 7.42-7.47 (m,3H); 7.94 (d, J=8.0 Hz, 2H); 9.28 (bs. 1H).

Example 46 Synthesis of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate

a) Preparation of ethyl4″-(acetylethylamino)-4′-(3-bromopropyl)-3″-tert-butyl[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 38a, by reacting 450 mg of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate(0.9 mmol) with 665 mg (1.8 mmol, 0.80 mL) of trioctylphosphine and 600mg (1.80 mmol) of carbon tetrabromide, 500 mg of ethyl4″-(acetylethylamino)-4′-(3-bromopropyl)-3″-tert-butyl[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=98%) in the form of an orange oil.

b) Synthesis of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 38b, by reacting 490 mg of ethyl4″-(acetylethylamino)-4′-(3-bromopropyl)-3″-tert-butyl[1,1′;3′,1″]terphenyl-4-carboxylate(0.87 mmol) with 0.6 mL of cyclopropylamine (9 mmol). 270 mg of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=57%) in the form of an orange-colored oil.

¹H NMR (CDCl₃, 400 MHz): 0.73 (m, 4H); 1.27 (t, J=6.8 Hz, 3H); 1.42 (s,9H); 1.44 (t, 3H); 1.87 (s, 3H); 1.89 (m, 2H); 2.48 (m, 1H); 2.73 (t,J=8.0 Hz, 2H); 2.86 (t, J=8.0 Hz, 2H); 2.97 (m, 1H); 3.89 (m, 2H); 4.42(q, J=7.4 Hz, 2H); 7.12 (d, J=8.0 Hz, 1H); 7.25 (m, 1H); 7.50-7.53 (m,3H); 7.58-7.62 (m, 1H); 7.68 (d, J=8.0 Hz, 2H); 8.11 (d, J=8.0 Hz, 2H).

Example 47 Synthesis of4″-(acetylethylamino)-3″-tert-butyl-4′(3-cyclopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 260 mg of ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate(0.48 mmol) with 2 mL of 1N sodium hydroxide solution, 100 mg of4″-(acetylethylamino)-3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=41%) in the form of a white solid (m.p.=190°C.).

¹H NMR (CDCl₃, 400 MHz): 0.73 (m, 4H); 1.26 (t, J=6.8 Hz, 3H); 1.42 (s,9H); 1.87 (s, 3H); 1.89 (m, 2H); 2.48 (m, 1H); 2.73 (t, J=8.0 Hz, 2H);2.86 (t, J=8.0 Hz, 2H); 2.97 (m, 1H); 4.34 (m, 1H); 7.12 (d, J=8.0 Hz,1H); 2.58 (dd, J₁=2.0 Hz, J₂=8.0 Hz, 1H); 7.35 (d, J=8.0 Hz, 1H); 7.49(d, J=2.0 Hz, 1H); 7.51 (dd, J₁=2.0 Hz, J₂=8.0 Hz, 1H); 7.58-7.62 (m,3H); 8.00 (d, J=8.0 Hz, 2H).

Example 48 Synthesis of ethyl3″-tert-butyl-4″-diethylamino-4′-(3-isopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate

In a manner similar to that of Example 38b, by reacting 600 mg of ethyl4′-(3-bromopropyl)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate(1.1 mmol) with 0.93 mL of isopropylamine (11 mmol), 353 mg of ethyl3″-tert-butyl-4′-(3-isopropylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylateare obtained (yield=57%) in the form of a white solid.

¹H NMR (CDCl₃, 400 MHz): 1.16 (t, J=7.2 Hz, 6H); 1.37 (d, J=6.8 Hz, 6H);1.42 (t, 3H); 1.48 (s, 9H); 2.20-2.25 (m, 2H); 2.75-2.79 (m, 4H); 2.93(bs, 2H); 3.00 (bs, 2H); 3.28 m, 1H); 4.41 (q, J=7.5 Hz, 2H); 7.15 (d,J=2.0 Hz, 1H); 7.30 (dd, J₁=2.1 Hz, J₂=8.3 Hz, 2H); 7.44-7.55 (m, 3H);7.65 (d, J=8.0 Hz, 2H); 8.09 (d, J=8.0 Hz, 2H); 8.98 (bs, 1H).

Example 49 Synthesis of3″-tert-butyl-4′-(3-isopropylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 350 mg of ethyl3″-tert-butyl-4′-(3-isopropylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate(0.67 mmol) with 2 mL of 1N sodium hydroxide solution, 200 mg of3″-tert-butyl-4′-(3-isopropylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=59%) in the form of a white solid (m.p.=253°C.).

¹H NMR (CD₃OD, 400 MHz): 1.23 (t, J=7.2 Hz, 6H); 1.37 (d, J=6.8 Hz, 6H);1.62 (s, 9H); 1.97 (m, 2H); 2.74 (m, 1H); 2.89-2.96 (m, 4H); 3.02 (m,2H); 3.14 (m, 2H); 7.35 (dd, J₁=2.0 Hz, 1H); 7.49-7.51 (m, 2H); 7.55 (d,J=8.0 Hz, 1H); 7.62 (d, J=2.0 Hz, 1H); 7.75 (dd, J₁=2.0 Hz, J₂=8.0 Hz,1H); 7.78 (d, J=8.0 Hz, 2H); 8.13 (d, J=8.0 Hz, 2H).

Example 50 Synthesis of ethyl3″-tert-butyl-4′-(3-aminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate

a) Preparation of ethyl3″-tert-butyl-4″-diethylamino-4′-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propyl]-[1,1′;3′,1″]terphenyl-4-carboxylate

In a 50 mL three-necked flask under a nitrogen atmosphere, equipped witha magnetic stirrer, 1.0 g (1.82 mmol) of ethyl4′-(3-bromopropyl)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate,294 mg (2 mmol) of isoindole-1,3-dione and 276 mg of potassium carbonate(2 mmol) are placed in 20 mL of dimethylformamide. The reaction mediumis heated at 100° C. for 3 hours and is then poured into waterbeforehand and acidified slightly with a 1 mol/L solution ofhydrochloric acid, and extracted twice with ethyl acetate. The organicphases obtained are combined and washed with water, dried over anhydrousmagnesium sulfate, filtered and evaporated to give a brownish oil. Thisoil is purified by chromatography on silica (eluent: 80/20 heptane/ethylacetate) to give 950 mg of ethyl3″-tert-butyl-4″-diethylamino-4′-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propyl]-[1,1′;3′,1″]terphenyl-4-carboxylate(yield=86%) in the form of a colorless oil.

b) Synthesis of ethyl3″-tert-butyl-4′-(3-aminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate

In a 50 mL three-necked flask under a nitrogen atmosphere, equipped witha magnetic stirrer, 900 mg (1.46 mmol) of ethyl3″-tert-butyl-4″-diethylamino-4′-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propyl]-[1,1′;3′,1″]terphenyl-4-carboxylateand 292 mg (5.8 mmol) of hydrazine hydrate are placed in 20 mL ofethanol. The reaction medium is heated to the reflux point of theethanol for 20 hours and then filtered; the filtrate obtained isevaporated and then purified directly on a column of silica (eluent:94/6 dichloromethane/methanol) to give, after evaporation of the purestfractions, 545 mg of ethyl3″-tert-butyl-4′-(3-aminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate(yield=77%) in the form of a colorless oil.

¹H NMR (CDCl₃, 400 MHz): 1.12 (t, J=7.2 Hz, 6H); 1.43 (t, J=7.5 Hz, 3H);1.50 (s, 9H); 1.63-1.69 (m, 2H); 2.61 (t, J=6.9 Hz, 2H); 2.70 (t, J=6.9Hz, 2H); 2.90 (bs, 2H); 2.95 (bs, 2H); 4.42 (q, J=7.5 Hz, 2H); 7.18 (m,1H); 7.28-7.32 (m, 1H); 7.38 (d, J=2.0 Hz, 1H); 7.40 (d, J=8.3 Hz, 1H);7.55-7.59 (m, 2H); 7.71 (d, J=6.8 Hz, 2H); 8.11 (d, J=6.8 Hz, 2H).

Example 51 Synthesis of3″-tert-butyl-4′-(3-aminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylicacid

In a manner similar to that of Example 3, by reacting 545 mg of ethyl3″-tert-butyl-4′-(3-aminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate(1.1 mmol) with 4 mL of 1N sodium hydroxide solution, 282 mg of3″-tert-butyl-4′-(3-aminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylicacid are obtained (yield=55%) in the form of a white solid (m.p.=272°C.).

¹H NMR (CDCl₃+εCD₃COOD, 400 MHz): 1.11 (t, J=7.2 Hz, 6H); 1.47 (s, 9H);1.91 (m, 2H); 2.72 (t, J=7.2 Hz, 2H); 2.84 (t, J=7.6 Hz, 2H); 2.92 (m,2H); 3.00 (m, 2H); 7.14 (dd, J₁=2.0 Hz, J₂=8.0 Hz, 1H); 7.31 (m, 2H);7.38 (d, J=7.6 Hz, 1H); 7.52-7.56 (m, 2H); 7.70 (d, J=8.4 Hz, 2H); 8.12(d, J=8.4 Hz, 2H).

Example 52 Synthesis of[3″-tert-butyl-4-carboxy-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4″-yl]diethylaminehydrochloride

0.7 g of3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid (1.5 mmol, 1 eq) obtained in Example 33 are dissolved at roomtemperature in 7 mL of Et₂O (10 vol) and 7 ml of ethanol, and 0.14 mL ofHCl (1.6 mmol, 1.1 eq) is then added.

The reaction mixture is then stirred for 5 hours.

Crystallization is performed in THF.

0.3 g of[3″-tert-butyl-4-carboxy-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4″-yl]diethylaminehydrochloride is obtained (yield=41%), (m.p.=164-166° C.).

¹H NMR (Methanol, 400 MHz)

1.36 (m, 6H); 1.61 (s, 9H); 1.72 (m, 2H); 1.68 (m, 1H); 2.71 (m, 2H);3.47 (t, 6.3 Hz, 2H); 3.74 (m, 1H); 3.90 (m, 2H); 3.99 (m, 2H); 7.50 (d,8.04 Hz, 1H); 7.53 (d, 1.30 Hz, 1H); 7.58 (d, 7.8 Hz, 1H); 7.70 (m, 5.52Hz, 2H); 7.76 (d, 8.2 Hz, 2H); 7.81 (d, 1H); 8.10 (d, 8.2 Hz, 2H).

Example 53 Synthesis of3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-(2-oxopyrrolidin-1-yl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

a) Preparation of N-(2-tert-Butyl-4-bromophenyl)-4-chlorobutanamide

20 g (0.0877 mol; 1 eq.) of 2-tert-butyl-4-bromoaniline (preparedaccording to Example 1a)) are dissolved in 100 ml of dichloromethane atabout 0° C.

13 ml (0.0921 mol; 1.05 eq.) of triethylamine are added, followed, after15 minutes, by addition of 10.5 ml (0.0921 mol; 1.05 eq.) of4-chlorobutanoyl chloride.

At the end of the addition, the reaction medium is returned to roomtemperature and stirred for 1 hour 30 minutes. 70 ml of H₂O are addedand the reaction medium is then allowed to settle. The aqueous phase isre-extracted with dichloromethane, and the organic phases are collectedand washed successively with aqueous 1M NaHCO₃ and then with H₂O.

The resulting organic phase is dried over sodium sulfate, filtered andconcentrated on a rotavapor.

An orange crystalline powder (m=31 g) is obtained, which, afterrecrystallization from heptane/ethyl acetate medium, gives 24 g ofN-(2-tert-butyl-4-bromophenyl)-4-chlorobutanamide (yield=82%).

b) Preparation of 1-(-2-tert-butyl-4-bromophenyl)pyrrolidin-2-one

24 g (0.0721 mol; 1 eq.) ofN-(2-tert-butyl-4-bromophenyl)-4-chlorobutanamide (obtained from stepa)) are suspended in 170 ml of absolute ethanol.

This suspension is cooled to about 0° C., and 60 ml (0.155 mol; 2.2 eq.)of sodium ethoxide as a 21% w/w solution in ethanol are added slowly.The reaction medium is then brownish-colored; it is stirred for 15 hoursat room temperature. 200 ml of H₂O are added and the mixture isextracted with heptane/ethyl acetate and washed with H₂O until theaqueous phase is neutral. The organic phase is concentrated on arotavapor: 20 g of an orange crystalline powder are isolated andrecrystallized from 200 ml of diisopropyl ether. Finally, 16 g of1-(-2-tert-butyl-4-bromophenyl)pyrrolidin-2-one are obtained(yield=75%).

c) Preparation of1-[2-tert-butyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]pyrrolidin-2-one

6.5 g (0.022 mol; 1 eq.) of1-(-2-tert-butyl-4-bromophenyl)pyrrolidin-2-one (obtained in step b)),5.85 g (0.023 mol; 1.05 eq.) of bis(pinacolato)diborane and 6.46 g(0.066 mol; 3 eq.) of potassium acetate are suspended in 50 ml ofdimethylformamide. After bubbling nitrogen into the reaction medium for15 minutes, 540 mg (0.66 mmol; 0.03 eq.) of catalyst (PdCl₂(dppf)) areadded and the medium is then heated at 90° C. until the reaction iscomplete.

The reaction medium cooled to room temperature and filtered through asinter funnel packed with Celite; the filter cake is rinsed thoroughlywith ethyl acetate, and H₂O is added to the filtrate, which is thenallowed to settle. The organic phase obtained is then concentrated on arotavapor to give a residue, which is purified by chromatography onsilica.

5.7 g of1-[2-tert-butyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]pyrrolidin-2-oneare isolated in the form of a white powder (yield=75%).

d) Preparation of ethyl[3′-bromo-4′-(2-hydroxyethoxy)]biphenyl-4-benzoate

70 g (0.218 mol; 1 eq.) of ethyl[3′-bromo-4′-hydroxy]biphenyl-4-benzoate are suspended with 45.2 g(0.327 mol; 1.5 eq.) of potassium carbonate, in 700 ml of methyl ethylketone.

39 ml (0.545 mol; 2.5 eq.) of 2-bromoethanol are added in a singleportion, and this suspension is heated to reflux. The reaction medium ismaintained under these conditions for 14 hours and then cooled to roomtemperature.

The reaction medium is filtered and the filtrate is concentrated. Theresidue is added to ethyl acetate, washed with H₂O and once againconcentrated. 90 g of a powder are obtained, which product isrecrystallized from heptane/ethyl acetate to give after drying 65 g ofethyl [3′-bromo-4′-(2-hydroxyethoxy)]biphenyl-4-benzoate, in the form ofa white crystalline powder (yield=82%).

f) Preparation of [3′-bromo-4′-(2-hydroxyethoxy)]biphenyl-4-carboxylicacid

63 g (0.173 mol; 1 eq.) of ethyl[3′-bromo-4′-(2-hydroxyethoxy)]biphenyl-4-benzoate (obtained in step d))are dissolved in 300 ml of tetrahydrofuran. 10.9 g (0.259 mol; 1.5 eq.)of lithium hydroxide monohydrate as a solution in 70 ml of H₂O are addedat room temperature.

The reaction medium is refluxed for about 1 hour 30 minutes.

The reaction medium is then cooled to room temperature and dilutehydrochloric acid solution is added (330 ml; ˜1M).

100 ml of H₂O are added and this suspension is cooled to about 0° C.; itis maintained at this temperature for about 15 minutes then filtered.After drying, 59 g of a white powder are obtained.

This product is slurried in 240 ml of acetone for two hours at roomtemperature and then filtered and oven-dried. 55 g of[3′-bromo-4′-(2-hydroxyethoxy)]biphenyl-4-carboxylic acid are thusisolated (yield=95%).

g) Synthesis of3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-(2-oxopyrrolidin-1-yl)-[1,1′,3′,1″]terphenyl-4-carboxylicacid

1.3 g (3.78 mmol; 1 eq.) of1-[2-tert-butyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]pyrrolidin-2-one(obtained in step c)) and 1.68 g (4.98 mmol; 1.3 eq.) of[3′-bromo-4′-(2-hydroxyethoxy)]biphenyl-4-carboxylic acid (obtained instep e)) are dissolved in 8 ml of dimethylformamide. 7.5 ml (0.015 mol;3.97 eq.) of aqueous 2M potassium carbonate solution and 35 mg (0.10mmol; 0.026 eq.) of 2-dicyclohexylphosphinobiphenyl are then added.

A stream of nitrogen is bubbled through the medium for about 10 minutes,and 11 mg (0.08 mmol; 0.014 eq.) of palladium acetate are introduced.The mixture is then heated to about 90° C. and maintained under theseconditions for 4-6 hours.

The reaction medium is then cooled to room temperature, filtered througha sinter funnel packed with Celite and rinsed with a minimum amount ofdimethylformamide, and dilute hydrochloric acid solution (˜2M) is addedto the filtrate.

After stirring for 4 hours, the precipitate formed is filtered off,rinsed to neutrality with H₂O, filtered off by suction and oven-dried.1.05 g of3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-(2-oxopyrrolidin-1-yl)-[1,1′,3′,1″]terphenyl-4-carboxylicacid are thus isolated (yield=57%).

Example 54 Synthesis of3″-tert-butyl-4″-ethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid

a) Preparation of N-(2-tert-butyl-4-bromophenyl)acetamide

18 g (0.079 mol; 1 eq.) of 2-tert-butyl-4-bromoaniline (preparedaccording to Example 1a)) are dissolved in 150 ml of dichloromethane atabout 0° C. 12.1 ml (0.087 mol; 1.1 eq.) of triethylamine are added,followed, after 15 minutes, by addition of 6.2 ml (0.087 mol; 1.1 eq.)of acetyl chloride. The mixture is warmed to room temperature at the endof addition and stirred for 2 hours. 70 ml of H₂O are added and theresulting mixture is allowed to settle. The aqueous phase isre-extracted with dichloromethane, and the organic phases are combined,washed to neutrality with H₂O, dried over sodium sulfate, filtered andconcentrated on a rotavapor.

21 g of a beige-colored crystalline powder are obtained, which productis slurried in heptane for 2 hours at room temperature, chilled and thenfiltered. After drying, 17.6 g ofN-(2-tert-butyl-4-bromophenyl)acetamide are obtained (yield=83%).

b) Preparation of (2-tert-butyl-4-bromophenyl)ethylamine

17.5 g (0.065 mol; 1 eq.) of N-(2-tert-butyl-4-bromophenyl)acetamide(obtained in step a)) are suspended in 100 ml of tetrahydrofuran.

162 ml (0.162 mol; 2.5 eq.) of 1M borane-tetrahydrofuran complex areadded and the mixture is heated to reflux. The conditions are maintainedfor about 12 hours.

The reaction mixture is cooled to room temperature and 70 ml of methanolare added to destroy the excess borane. The mixture is stirred until theevolution of gas has ceased and is then concentrated on a rotavapor. Theoil obtained is dissolved in ethyl acetate and washed with saturatedaqueous ammonium chloride solution and then with H₂O.

The resulting solution is concentrated and purified by filtration onsilica; 13 g of (2-tert-butyl-4-bromophenyl)ethylamine are thus obtainedin the form of a relatively colorless oil (yield=78%).

c) Preparation of[2-tert-butyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]ethylamine

13 g (0.0507 mol; 1 eq.) of (2-tert-butyl-4-bromophenyl)ethylamine(obtained in step b)), 15.5 g (0.061 mol; 1.2 eq.) ofbis(pinacolato)diborane and 15 g (0.152 mol; 3 eq.) of potassium acetateare suspended in 75 ml of dimethylformamide. After bubbling a stream ofnitrogen through the reaction medium for 15 minutes, 1.66 g (2.03 mmol;0.04 eq.) of catalyst (PdCl₂(dppf)) are added and the medium is heatedat about 90° C. for about 10 hours.

The reaction medium is cooled to room temperature and filtered through asinter funnel packed with Celite; the filter cake is rinsed thoroughlywith ethyl acetate, and H₂O is added to the filtrate and the phases areallowed to separate by settling. The organic phase obtained is thusconcentrated on a rotavapor to give a residue, which is chromatographedon a column of silica. 7 g of[2-tert-butyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]ethylamineare isolated in the form of an orange crystalline powder (yield=45%).

d) Preparation of ethyl[3′-bromo-4′-(3-hydroxypropoxy)]biphenyl-4-benzoate

47 g (0.146 mol; 1 eq.) of ethyl[3′-bromo-4′-hydroxy]biphenyl-4-benzoate are suspended with 30.3 g(0.219 mol; 1.5 eq.) of potassium carbonate in 470 ml of methyl ethylketone. 13.5 ml (0.154 mol; 1.05 eq.) of 3-bromopropan-1-ol are added ina single portion and this suspension is brought to reflux. Theseconditions are maintained for 14 hours and the mixture is then cooled toroom temperature. The medium is filtered and the filtrate isconcentrated. The residue is taken up in ethyl acetate, washed with H₂Oand then concentrated again. 60 g of a powder are isolated, and arerecrystallized from a heptane/ethyl acetate mixture to give, afterdrying, 40 g of ethyl[3′-bromo-4′-(3-hydroxypropoxy)]biphenyl-4-benzoate in the form of anoff-white crystalline powder (yield=72%).

e) Preparation of ethyl[3′-bromo-4′-(3-acetoxypropoxy)]biphenyl-4-benzoate

2 g (5.27 mmol; 1 eq.) of ethyl[3′-bromo-4′-(3-hydroxypropoxy)]biphenyl-4-benzoate (obtained in stepd)) are dissolved in 20 ml of dichloromethane. 64 mg (0.527 mmol; 0.1eq.) of 4-dimethylaminopyridine and 430 μl (5.27 mmol; 1 eq.) ofpyridine are added at room temperature. The mixture is stirred for 15minutes at room temperature, and 750 μl (7.91 mmol; 1.5 eq.) of aceticanhydride are then added. The mixture is maintained at room temperaturefor 1 hour. H₂O is added, the phases are allowed to separate by settlingand the organic phase is neutralized with aqueous 1M NHCO₃ solution. Theresulting organic phase is washed with H₂O until neutral andconcentrated on a rotavapor. 2.2 g of a powder are obtained, and arerecrystallized from a heptane/ethyl acetate mixture. This gives, afterdrying, 1.9 g of ethyl[3′-bromo-4′-(3-acetoxypropoxy)]biphenyl-4-benzoate in the form of awhite crystalline powder (yield=85%).

f) Preparation of ethyl4′-(3-acetoxypropoxy)-3″-tert-butyl-4″-ethylamino[1,1′,3′,1″]terphenyl-4-benzoate

720 mg (2.3 mmol; 1 eq.) of[2-tert-butyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenyl]ethylamine(obtained in step c)) and 1 g (2.3 mmol; 1 eq.) of ethyl[3′-bromo-4′-(3-acetoxypropoxy)]biphenyl-4-benzoate (obtained in stepe)) are dissolved in 10 ml of dimethylformamide. 2.5 ml (5 mmol; 2 eq.)of aqueous 2M tribasic potassium phosphate solution and 16.1 mg (0.046mmol; 0.02 eq.) of 2-dicyclohexylphosphinobiphenyl are added at roomtemperature.

After bubbling a stream of nitrogen into the medium for about 10minutes, 5.2 mg (0.023 mmol; 0.01 eq.) of palladium acetate are addedand the mixture is heated at 80° C. for about 5 hours. The reactionmedium is filtered through a sinter funnel packed with Celite and rinsedthoroughly with ethyl acetate. Saturated aqueous ammonium chloridesolution is then added to the filtrate, the phases are allowed toseparate by settling and the organic phase is washed with H₂O and thendried over sodium sulfate. The organic phase is concentrated; the oilobtained is chromatographed on a column of silica, and 900 mg of ethyl4′-(3-acetoxypropoxy)-3″-tert-butyl-4″-ethylamino[1,1′,3′,1″]terphenyl-4-benzoateare isolated (yield=73%).

g) Synthesis of3″-tert-butyl-4″-ethylamino-4′-(3-hydroxypropoxy)-[1,1′,3′,1″]terphenyl-4-carboxylicacid

900 mg (1.74 mmol; 1 eq.) of ethyl4′-(3-acetoxypropoxy)-3″-tert-butyl-4″-ethylamino-[1,1′,3′,1″]terphenyl-4-benzoateare dissolved in 10 ml of absolute ethanol. 312 mg (7.8 mmol; 4.5 eq.)of sodium hydroxide and 4 ml of H₂O are added at room temperature andthe mixture is then heated to reflux. These conditions are maintainedfor about 1 hour 30 minutes. The reaction medium is concentrated to asmall volume; H₂O is added to the precipitate formed, and the mixture isthen acidified with acetic acid to pH ˜4-5. This suspension is fluidizedby adding H₂O and stirred at room temperature for 1 hour. The resultingmixture is filtered through a sinter funnel, rinsed with H₂O until thefiltrate is neutral, and oven-dried. 694 mg of3″-tert-butyl-4″-ethylamino-4′-(3-hydroxypropoxy)-[1,1′,3′,1″]terphenyl-4-carboxylicacid are thus obtained in the form of a white powder (yield=89%).

Example 55 Transactivation Test

The activation of receptors with an agonist (activator) in HeLa cellsleads to the expression of a reporter gene, luciferase, which, in thepresence of a substrate, generates light. The activation of thereceptors may thus be measured by quantifying the luminescence producedafter incubating the cells in the presence of a reference agonist. Theinhibitory products displace the agonist from its site, thus preventingactivation of the receptor. The activity is measured by quantifying thereduction in light produced. This measurement makes it possible todetermine the inhibitory activity of the compounds according to theinvention.

In this study, a constant is determined which is the affinity of themolecule for the receptor. Since this value can fluctuate depending onthe basal activity and the expression of the receptor, it is referred toas the Kd apparent (KdApp).

To determine this constant, “crossed curves” of the test product againsta reference agonist,4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoicacid, are performed in 96-well plates. The test product is used at 10concentrations and the reference agonist at 7 concentrations. In eachwell, the cells are in contact with a concentration of the test productand a concentration of the reference agonist,4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoicacid. Measurements are also taken for the total agonist(4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoicacid) and inverse agonist,4-{(E)-3-[4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}benzoicacid, controls.

These crossed curves make it possible to determine the AC₅₀ values(concentration at which 50% activation is observed) for the referenceligand at various concentrations of test product. These AC₅₀ values areused to calculate the Schild regression by plotting a straight linecorresponding to the Schild equation (“quantitation in receptorpharmacology” Terry P. Kenakin, Receptors and Channels, 2001, 7,371-385).

The HeLa cell lines used are stable transfectants containing theplasmids ERE-βGlob-Luc-SV-Neo (reporter gene) and RAR (α, β, γ)ER-DBD-puro. These cells are inoculated into 96-well plates at a rate of10,000 cells per well in 100 μl of DMEM medium without phenol red, andsupplemented with 10% defatted calf serum. The plates are then incubatedat 37° C. and 7% CO₂ for 4 hours.

The various dilutions of the test products, of the reference ligand(4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoicacid), of the 100% control (100 nM4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoicacid) and of the 0% control (500 nM4-{(E)-3-[4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}benzoicacid) are added at a rate of 5 μl per well. The plates are thenincubated for 18 hours at 37° C. and 7% CO₂.

The culture medium is removed by turning over and 100 μl of a 1:1PBS/luciferin mixture is added to each well. After 5 minutes, the platesare read using the luminescence reader.

RARalpha RARbeta RARgamma Kdapp (nM) Kdapp (nM) Kdapp (nM) Compound ofExample 3 30 8 2 Compound of Example 5 8 8 0.5 Compound of Example 6 608 0.25 Compound of Example 8 60 4 0.12 Compound of Example 12 250 4 2Compound of Example 13 500 4 0.5 Compound of Example 17 250 8 30Compound of Example 19 60 4 1 Compound of Example 21 4 4 30 Compound ofExample 23 60 8 2 Compound of Example 25 500 15 2 Compound of Example 3360 8 0.5 Compound of Example 35 4000 500 8 Compound of Example 37 250120 30 Compound of Example 47 120 250 120 Compound of Example 52 30 20.25 Compound of Example 53 2000 8000 60 Compound of Example 54 8 4 0.25

The results obtained with the compounds according to the inventionclearly show Kdapp values of less than or equal to 1000 nM.

Example 56 Formulation Examples

This example illustrates various specific formulations based on thecompounds according to the invention.

A—Oral Route:

(a) 0.2 g Tablet:

Compound of Example 5 0.001 g Starch 0.114 g Dicalcium phosphate 0.020 gSilica 0.020 g Lactose 0.030 g Talc 0.010 g Magnesium stearate 0.005 g

(b) Drinkable Suspension in 5 ml Ampoules:

Compound of Example 3 0.001 g Glycerol 0.500 g 70% sorbitol 0.500 gSodium saccharinate 0.010 g Methyl para-hydroxybenzoate 0.040 gFlavouring qs Purified water qs 5 ml

(c) 0.8 g Tablet:

Compound of Example 4 0.500 g Pregelatinized starch 0.100 gMicrocrystalline cellulose 0.115 g Lactose 0.075 g Magnesium stearate0.010 g

(d) Drinkable Suspension in 10 ml Ampoules:

Compound of Example 2 0.200 g Glycerol 1.000 g 70% sorbitol 1.000 gSodium saccharinate 0.010 g Methyl para-hydroxybenzoate 0.080 gFlavoring qs Purified water qs 10 ml

B—Parenteral Route:

(a) Composition:

Compound of Example 3 0.002 g Ethyl oleate qs 10 g

(b) Composition:

Compound of Example 1 0.05% Polyethylene glycol   20% 0.9% NaCl solutionqs 100

(c) Composition:

Compound of Example 3 2.5% Polyethylene glycol 400  20% 0.9% NaClsolution qs 100

(d) Injectable Cyclodextrin Composition:

Compound of Example 3 0.1 mg β-Cyclodextrin 0.10 g Water for injectionqs 10.00 g

C—Topical Route:

(a) Ointment:

Compound of Example 2 0.020 g Isopropyl myristate 81.700 g  Liquidpetroleum jelly oil 9.100 g Silica (“Aerosil 200” marketed by Degussa)9.180 g

(b) Ointment:

Compound of Example 5 0.300 g White petroleum jelly codex qs 100 g

(c) Nonionic Water-in-oil Cream:

Compound of Example 4 0.100 g Mixture of emulsifying lanolin alcohols,waxes and 39.900 g oils (“Anhydrous Eucerin” marketed by BDF) Methylpara-hydroxybenzoate 0.075 g Propyl para-hydroxybenzoate 0.075 g Steriledemineralized water qs 100 g

(d) Lotion:

Compound of Example 2  0.100 g Polyethylene glycol (PEG 400) 69.900 g95% ethanol 30.000 g

(e) Hydrophobic Ointment:

Compound of Example 4  0.300 g Isopropyl myristate 36.400 g Silicone oil(“Rhodorsil 47 V 300” marketed by 36.400 g Rhône-Poulenc) Beeswax 13.600g Silicone oil (“Abil 300 000 cSt” marketed by qs 100 g Goldschmidt)

(f) Nonionic Oil-in-water Cream:

Compound of Example 5 1.000 g Cetyl alcohol 4.000 g Glycerylmonostearate 2.500 g PEG 50 stearate 2.500 g Shea butter 9.200 gPropylene glycol 2.000 g Methyl para-hydroxybenzoate 0.075 g Propylpara-hydroxybenzoate 0.075 g Sterile demineralized water qs 100 g

Each patent, patent application, publication, text and literaturearticle/report cited or indicated herein is hereby expresslyincorporated by reference.

While the invention has been described in terms of various specific andpreferred embodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

1. A method for treating a dermatological condition selected from thegroup consisting of acne vulgaris, comedonic acne, polymorphic acne,nodulocystic acne, acne conglobata and secondary acne, said methodcomprising administering to an individual in need of such treatment, aneffective amount of a pharmaceutical composition comprising apharmaceutically effective amount of at least one ligand compound havingthe formula (I) below:

in which: R₁ is a hydrogen atom, an alkyl radical of 1 to 4 carbon atomsor a —CF₃ radical; R₂ is a hydrogen atom, an alkyl or alkoxy radical of1 to 4 carbon atoms or a chlorine atom; R₃ is a hydrogen atom or alinear or branched alkyl or alkoxy radical of 1 to 10 carbon atomsoptionally substituted with a methoxy group; R₄ is a hydrogen atom or analkyl radical of 1 to 3 carbon atoms; R₅ is a hydrogen atom or an alkylradical of 1 to 3 carbon atoms; or alternatively R₄ and R₅ form,together with the bond —N—C(═Y)—, a pyrrolidine, pyrrolidinone,piperidine or piperidinone ring; Y is two hydrogen atoms or a heteroatom; Ar is a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenylring; X is an oxygen atom optionally substituted with an alkyl oralkylamine radical or a C—C single bond; and A is a hydrogen atom or thefollowing formula:

in which: Q is an oxygen atom or an —NH— bond; R₆ is a hydrogen atom, analkyl radical of 1 to 6 carbon atoms, a cycloalkyl radical of 3 to 6carbon atoms or a —C(O)CH₃ or —C(O)CH₂CH₃ radical; R₇ and R₇′ represent,independently of each other, a hydrogen atom or a hydroxyl group, withthe provisio that R₇ and R₇′ are not simultaneously a hydroxyl group;and n is 0, 1, 2, 3, 4 or 5; or a salt of a compound of formula (I) whenR₃ is a hydrogen atom, or a geometrical isomer of a compound of formula(I); formulated into a pharmaceutically and physiologically acceptablemedium therefor.
 2. The method as defined by claim 1, wherein, informula (I), R₁ is a —CF₃ radical.
 3. The method as defined by claim 1,wherein, in formula (I), Ar is a 1,4-phenyl ring.
 4. The method asdefined by claim 1, wherein, in formula (I), Ar is a 2,5-pyridyl ring.5. The method as defined by claim 1, wherein, in formula (I), Ar is a5,2-pyridyl ring.
 6. The method as defined by claim 1, wherein, informula (I), Ar is a 2,5-thiophenyl ring.
 7. The method as defined byclaim 1, wherein, in formula (I), Y is oxygen.
 8. The method as definedby claim 1, wherein, in formula (I), Y is sulfur.
 9. The method asdefined by claim 1, wherein, in formula (I), R₄ and R₅ together form,with the —N—C(═Y)-radical, a pyrrolidine, pyrrolidinone, piperidine orpiperidinone ring.
 10. The method as defined by claim 1, wherein thecompound is an alkali metal or alkaline-earth metal salt, a zinc salt ora salt of an organic amine or of an acidic partner when the compound isitself basic.
 11. The method as defined by claim 1, wherein the alkylradical of 1 to 3 carbon atoms is selected from the group consisting ofmethyl, ethyl, i-propyl and n-propyl radicals.
 12. The method as definedby claim 1, wherein the alkyl radical of 1 to 4 carbon atoms is selectedfrom the group consisting of methyl, ethyl, i-propyl, i-butyl andt-butyl radicals.
 13. The method as defined by claim 1, wherein thealkyl radical of 1 to 10 carbon atoms is selected from the groupconsisting of methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,pentyl, hexyl, heptyl, octyl, nonyl and dodecyl radicals.
 14. The methodas defined by claim 1, wherein the alkoxy radical having from 1 to 10carbon atoms is selected from the group consisting of methoxy, ethoxy,isopropyloxy, tert-butoxy and hexyloxy radicals.
 15. The method asdefined by claim 1, wherein the alkoxy radical having from 1 to 4 carbonatoms is selected from the group consisting of methoxy, ethoxy,isopropyloxy and tert-butoxy radicals.
 16. The method as defined byclaim 1, wherein the cycloalkyl radical of 3 to 6 carbon atoms isselected from the group consisting of cyclopropyl, cyclopentyl andcyclohexyl radicals.
 17. The method as defined by claim 1, wherein theligand compound having formula (I) is selected from the group consistingof:
 1. ethyl3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylate,2. ethyl3″-tert-butyl-4″-diethylamino-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate,3.3″-tert-butyl-4″-diethylamino-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 4. ethyl 4″-(acetylethylamino)-3″-tert-butyl-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate, 5.4″-(acetylethylamino)-3″-tert-butyl-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid, 6.3″-tert-butyl-4″-diethylamino-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 7. ethyl3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate, 8.3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 9. ethyl4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate,10.4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 11. ethyl4″-diethylamino-3″-ethyl-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate,12.4″-diethylamino-3″-ethyl-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid, 13.4″-diethylamino-3″-ethyl-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 14. ethyl4″-diethylamino-3″-ethyl-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate,15. ethyl3″-tert-butyl-4″-diethylamino-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate,16. ethyl4″-diethylamino-4′-(3-hydroxypropoxy)-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylate,17.4″-diethylamino-4′-(3-hydroxypropoxy)-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 18. ethyl3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate,19.3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 20. ethyl4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylate,21.4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 22. ethyl3″-tert-butyl-4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate, 23.3″-tert-butyl-4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 24. ethyl3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate,25.3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid, 26.4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid, 27.3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 28. ethyl4″-diethylamino-4′-hydroxy-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylate,29.4″-diethylamino-4′-hydroxy-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylicacid, 30.3″-tert-butyl-4″-diethylamino-4′-(4isopropylaminobutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic acid, 31.3″-tert-butyl-4′-(4-isopropylaminobutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic acid,
 32. ethyl3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate,33.3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 34. ethyl 3″-tert-butyl-4″-diethylamino-4′-(2,3-dihydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate, 35.3″-tert-butyl-4″-diethylamino-4′-(2,3-dihydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 36. ethyl 4″-(acetylethylamino)-3″-tert-butyl-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate, 37.4″-(acetylethylamino)-3″-tert-butyl-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 38. ethyl3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate,39.3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylic acid,
 40. ethyl3″-tert-butyl-4′-(3-cyclopentylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate,41.3″-tert-butyl-4′-(3-cyclopentylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylic acid,
 42. ethyl3″-tert-butyl-4′-(3-cyclohexylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate,43.3″-tert-butyl-4′-(3-cyclohexylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylic acid,
 44. ethyl3″-tert-butyl-4′-(3-tert-butylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate,45.3″-tert-butyl-4′-(3-tert-butylaminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 46. ethyl4″-(acetylethylamino)-3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate, 47.4″-(acetylethylamino)-3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylic acid,
 48. ethyl3″-tert-butyl-4″-diethylamino-4′-(3-isopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate, 49.3″-tert-butyl-4″-diethylamino-4′-(3-isopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylic acid,
 50. ethyl4′-(3-aminopropyl)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate,51.4′-(3-aminopropyl)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylicacid, 52.[3″-tert-butyl-4-carboxy-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4″-yl]diethylaminehydrochloride, 53.3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-(2-oxopyrrolidin-1-yl)-[1,1′;3′,1″]terphenyl-4-carboxylic acid, 54.3″-tert-butyl-4″-ethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid, 55.4′-(3-acetoxypropoxy)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylicacid, 56.3″-tert-butyl-4″-diethylamino-4′-(3-propionyloxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 57. methyl 3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate,
 58. isopropyl3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate,
 59. isobutyl3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate, 60.3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropoxy)-5″-methyl[1,1′;3′,1″]terphenyl-4-carboxylicacid, 61.4″-diethylamino-4′-(3-hydroxypropoxy)-3″-isopropyl-5″-methyl[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 62. 3″-tert-butyl-5″-chloro-4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic acid, 63.4″-diethylamino-4′-(3-hydroxypropoxy)-3″,5″-diisopropyl[1,1′;3′,1″]terphenyl-4-carboxylicacid, 64.3″,5″-di-tert-butyl-4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic acid, 65.4″-diethylamino-4′-(3-hydroxypropoxy)-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylicacid, 66.3″-tert-butyl-4″-(ethylmethylamino)-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid, 67.3″-tert-butyl-4″-dimethylamino-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 68. 3″-tert-butyl-4″-(ethylisopropylamino)-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic acid, 69.3″-tert-butyl-4″-(ethylpropylamino)-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid, 70.3″-tert-butyl-4″-dipropylamino-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 71. 3″-tert-butyl-4″-(ethylpropionylamino)-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic acid, 72.6-[3′-tert-butyl-4′-diethylamino-6-(2-hydroxyethoxy)biphenyl-3-yl]nicotinicacid, 73.5-[3′-tert-butyl-4′-diethylamino-6-(2-hydroxyethoxy)biphenyl-3-yl]pyridine-2-carboxylicacid, 74.5-[3′-tert-butyl-4′-diethylamino-6-(2-hydroxyethoxy)biphenyl-3-yl]thiophene-2-carboxylicacid, 75.3″-tert-butyl-4′-(2-hydroxyethoxy)-5″-methyl-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid, 76.3″-tert-butyl-5″-chloro-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid, 77.4′-(2-hydroxyethoxy)-3″-isopropyl-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid, 78.3″-ethyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid, 79.4′-(2-hydroxyethoxy)-3″,5″-diisopropyl-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid, 80.3″,5″-diethyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid, 81.3″,5″-dimethyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid, 82.4′-(2-acetoxyethoxy)-3″-tert-butyl-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid, 83.4′-(2-propionyloxyethoxy)-3″-tert-butyl-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid,
 84. methyl3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate,
 85. isopropyl3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate,86. isobutyl3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate,
 87. ethyl3″-tert-butyl-4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate,
 88. ethyl3″-tert-butyl-5″-chloro-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate,89.6-[3′-tert-butyl-6-(2-hydroxyethoxy)-4′-pyrrolidin-1-ylbiphenyl-3-yl]nicotinicacid, 90.5-[3′-tert-butyl-6-(2-hydroxyethoxy)-4′-pyrrolidin-1-ylbiphenyl-3-yl]pyridine-2-carboxylicacid,
 91. ethyl6-[3′-tert-butyl-6-(2-hydroxyethoxy)-4′-pyrrolidin-1-ylbiphenyl-3-yl]nicotinate,92. ethyl3″-tert-butyl-4′-(3-hydroxypropyl)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate,93.3″-tert-butyl-4′-(3-hydroxypropyl)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid, 94.3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-(2-oxopyrrolidin-1-yl)-[1,1′;3′,1″]terphenyl-4-carboxylic acid, 95.3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-(2-oxopiperid-1-yl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid, 96.3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-piperid-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid, and 97.5-[3′-tert-butyl-6-(2-hydroxyethoxy)-4′-pyrrolidin-1-ylbiphenyl-3-yl]thiophene-2-carboxylicacid.
 18. The method as defined by claim 1, wherein, in formula (I), atleast one of the following conditions is satisfied: R₁ is a hydrogenatom or a t-butyl or i-propyl radical; R₂ is a hydrogen atom or at-butyl or i-propyl radical; R₃ is a hydrogen atom or an ethyl radical;R₄ and R₅ are, independently of each other, a methyl or ethyl radical ortogether form a pyrrolidine ring; A is as defined in which R₆ is ahydrogen atom, an i-propyl or t-butyl radical, a cycloalkyl radical of 3to 6 carbon atoms or a —C(O)CH₃ or —C(O)CH₂CH₃ radical.
 19. The methodas defined by claim 18, wherein, in formula (I), all of the followingconditions are satisfied: R₁ is a hydrogen atom or a t-butyl or i-propylradical; R₂ is a hydrogen atom or a t-butyl or i-propyl radical; R₃ is ahydrogen atom or an ethyl radical; R₄ and R₅ are, independently of eachother, a methyl or ethyl radical or together form a pyrrolidine ring; Ais as defined in which R₆ is a hydrogen atom, an i-propyl or t-butylradical, a cycloalkyl radical of 3 to 6 carbon atoms or a —C(O)CH₃ or—C(O)CH₂CH₃ radical.
 20. The method as defined by claim 1, wherein theligand compound having formula (I) is selected from the group consistingof:3″-tert-butyl-4″-diethylamino-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,4″-(acetylethylamino)-3″-tert-butyl-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,3″-tert-butyl-4″-diethylamino-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,4″-diethylamino-3″-ethyl-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,4″-diethylamino-3″-ethyl-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,4″-diethylamino-4′-(3-hydroxypropoxy)-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylicacid,3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid,4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl-3″-trifluoromethyl[1,1′;3′,1″]terphenyl-4-carboxylicacid,3″-tert-butyl-4′-(3-hydroxypropoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid,3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid,3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,3″-tert-butyl-4″-diethylamino-4′-(2,3-dihydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid,4″-(acetylethylamino)-3″-tert-butyl-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid, 4″-(acetylethylamino)-3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylic acid,[3″-tert-butyl-4-carboxy-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4″-yl]diethylaminehydrochloride,3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-(2-oxopyrrolidin-1-yl)-[1,1′;3′,1″]terphenyl-4-carboxylicacid, and3″-tert-butyl-4″-ethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylicacid.
 21. The regime or regimen as defined by claim 1, wherein theligand compound having formula (I) is3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylicacid.
 22. The method as defined by claim 1, wherein the individual is inneed of treatment for acne vulgaris.
 23. The method as defined by claim2, wherein the ligand compound having formula (I) is3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic acid.